TW201121958A - Methods of treating hepatitis C virus with oxoacetamide compounds - Google Patents

Abstract

Provided herein are hepatitis C virus entry inhibitor oxoacetamide compounds, pharmaceutical compositions thereof, and methods for their use in treatment or prevention of hepatitis C virus infection in a subject in need thereof.

Description

201121958 VI. Description of the Invention: [Technical Field] The present invention provides a hepatitis C virus entry inhibitor ketodecylamine compound, a pharmaceutical composition thereof and the same for treating or preventing hepatitis C virus infection in an individual in need thereof The method. [Prior Art] The major pathogenic virus of hepatitis after non-A and B type transfusion was discovered in 1989 and referred to as hepatitis C virus (HCV). Since then, several types of hepatitis viruses have been discovered in addition to type A, type B and type C, and hepatitis caused by HCV is called hepatitis C. Individuals infected with HCV are considered to be involved in a few percent of the world's population, and HCV infections become characteristically chronic. HCV is an enveloped RNA virus in which the genome is single strand plus-strand RNA and belongs to the genus Hepacivirus of the Flavivirus (International Committee on Taxonomy of Viruses). International Union of Microbiological Societies). In the same hepatitis virus, for example, the hepatitis B virus (HBV) which is a DNA virus is eliminated by the immune system, and the result of infecting the virus is acute infection, except for newborns and infants who have immature immunity. In contrast, HCV circumvents host immune systems in some way due to unknown mechanisms. Once infected with this virus, even adults with a mature immune system often develop persistent infections. When chronic hepatitis is associated with persistent HCV infection, it progresses to cirrhosis or liver cancer at a high rate. Surgical removal of tumors is not helpful because individuals often develop recurrent liver cancer due to inflammation of the non-cancerous partial sequelae. 152269.doc 201121958 'An effective treatment for the treatment of hepatitis C infection. In addition to the use of symptomatic treatments for inflammation, there is a strong demand for the development of therapeutic agents that reduce hcv to a low level of no inflammation and to remove HCV. The best therapeutic agent will provide a virological response to the classification = "permanent virological response", and the long-lasting virological response will be maintained for six months or more after completion of hepatitis C therapy. Measurement. Currently, no effective HCV vaccine has been identified. The only effective method currently known for removing HCV is to use interferon (eg or

Peglntron 9) is treated as a single agent or in combination with the nucleoside analog ribavirin. However, even the most effective HCV therapy (alpha interferon and ribavirin) produces long-lasting effects in only about 4% of patients (Poynard et al, J998, 352, 1426-1432). It has no effect or only a temporary effect for the remaining individual'. Therefore, there is a great need for an anti-Hcv drug to be used in place of or in parallel with interferon and/or viral saliva. Clinical and preclinical testing is being performed on various therapeutic strategies for HCV, including inhibition of protein processing or viral RNA replication. See, for example, Hugle et al., C. Met/. 2003, 13: 361-371. One such strategy common to the development of antiviral agents is the inactivation of virally encoded enzymes necessary for viral replication. For example, a possible treatment of NS3 protease inhibitors for HCV infection via a viral replication mechanism has been investigated. See Tan et al., WiMre i?ev. Z) b£^v., 2002, 1: 867-881. However, many of these agents lose efficacy due to drug resistance caused by high HCV mutation rates. See, for example, Zein et al., C/z «· Λ/ϊπο6ζ·ο/_i?ev., 2000, 13: 223-235. Thus, although 152269.doc 201121958 agents that target viral replication may be promising as HCV therapeutics, the development of agents that link viruses via alternative mechanisms remains an urgent issue for the foreseeable future. The emerging field of antiviral research is the field of small molecule entry inhibitors. Such drugs are designed to block entry of the virus into mammalian cells by interfering with various ligation and/or fusion phases between the virus and the cells. For example, two HIV entry inhibitors, enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), are commercially available, and many other inhibitors are being developed. in. See, for example, Reeves, JD, ENTRY INHIBITORS IN HIV THERAPY (Reeves, J. D., Derdeyn, CA, ed., Birkhauser 2007); Liu, S_ et al., /. 〇厂CTzem., 2005, 280: 11259-11273 . The development of HCV entry inhibitors will be more beneficial than current therapies for a number of reasons. HCV entry inhibitors can be used to meet current HCV treatment criteria, namely interferon and ribavirin, as these drugs act by alternative mechanisms. HCV entry inhibitors may be more effective in treating drug resistant HCV strains. Furthermore, the use of HCV entry inhibitors is less likely to develop resistance as the entry inhibitor targets the host cell rather than the virus itself. In view of the fact that HCV infection has reached global prevalence, novel and effective compositions such as HCV entry inhibitors are needed to treat or prevent hepatitis C infection. SUMMARY OF THE INVENTION Provided herein are hepatitis C virus entry inhibitor compounds, pharmaceutical compositions thereof, and methods for treating or preventing hepatitis C virus 152269.doc 201121958 infection in an individual in need thereof, without being limited to a particular mechanism of action, The compound can

匕 Provided herein are Hcv entry inhibitors and pharmaceutical compositions thereof, which are useful for treating or preventing HCV infection in an individual in need thereof. In certain embodiments, the Hcv entry inhibitor is selected from the group consisting of ketoguanamine compounds of the following general formula (1) or (Π):

R is methyl, ethyl, isopropyl, hydrazine or k/OH, R is 〇^-(:8 alkyl; C5-C8 cycloalkyl 4c7-c1()arylalkyl; R3 is hydrogen, Cyano, -CONHR6, -NHS02R7 or -S〇2N(R8)2; ... is a heart-fluorenyl group; r5 is c, -c4 alkoxy or -N(R8)2; R6 is 2-pyridyl or C"C6 alkyl, wherein one or more carbon atoms are optionally replaced by an oxygen atom; r7 is C丨-c4 alkyl, ch2cf3, benzyl or phenyl; and 152269.doc 201121958 ... is 匕-^alkyl ; R is desert or 6-(methylamino) oxime than bite 3_ base;

RlG is hydrogen or -CONHR11; and RU is hydrogen or C丨-C4 alkyl; the base constraint is that if "is ... then ... and the ruler 7 is methyl, then Ri is not a restriction condition if it is hydrogen, then Rule 9 is 6-(methylamino)β-pyridyl_3_ group; and the restriction is that if R11 is a cyclopropyl group, then R9 is indifferent. It should be understood that the compounds provided herein may contain a center of the palm. The center may be in the (R) or (S) configuration, or may be a mixture thereof. In some cases, the substituent of the compound of formula I may promote optical and/or stereoisomerization. 7 Thus, the compounds provided herein may be Pure enantiomeric, or a stereoisomeric or diastereomeric mixture. 'This document also provides a pharmaceutically acceptable salt of a compound of formula I. The compounds provided herein are substantially pure Form exists. As used herein, 'substantially pure' means sufficiently homogenous to appear 'without easily detectable impurities, such as thin layer chromatography (TLC) used by those skilled in the art to evaluate this purity. ), gel electrophoresis, high performance liquid chromatography (HPLC), nuclear magnetic resonance (NMR) & f spectrum analysis (ms) standard analysis Cloth measurement, or sufficiently pure '_ such that further purification would not be left foot into Zhen geodesic change their physical and chemical properties of the materials, such as enzymatic and biological activity. A method known to those skilled in the art for purifying a compound to produce a chemically pure compound on a substance H is a substantially chemically pure compound which may be a mixture of stereoisomers. In such cases, further purification increases the specific activity of the compound. 152269.doc 201121958 The present invention is meant to include all such possible isomers, as well as the racemic and optically pure forms thereof. The optically active (+) and (i), (R), and (8), or (8)· isomers can be prepared using a palm-forming synthetic component or a palmitic reagent, or using conventional techniques such as reverse phase HPLC. When a compound described herein contains a rare double bond or other geometrically asymmetric center, and unless otherwise specified, the compound is intended to include geometric isomers. Likewise, it is intended to include all tautomeric forms. Also provided herein are isotopically enriched analogs of the compounds provided herein. Some of the classes of drugs have previously been used to demonstrate the isotope enrichment (eg, aerosolization) of modified pharmacokinetics (rPK), pharmacodynamics ("pDj"), and toxic forms. See, for example, Lijinsky et al., 2: 393 (1982) ; Lijinsky et al., j 细^, 69: ιΐ27 (1982); Mangold et al., detail, 3〇8: 33 (Amount-Europe, etc.,--Lanru, 15 589 (]利; et al. 'Gal. 43: 487 (1994); Gately et al., 乂心 c/

Med., 27: 388 (1986); Wade D.} Chem. Biol. Interact., 117: 191 (1999). The isotope of the drug can be used to: for example, (1) reduce or eliminate undesired metabolites, (2) increase the half-life of the parent drug, (3) reduce the number of doses required to achieve the desired effect, (4) reduce the achievement The amount of dose necessary to effect the desired effect, (7) increase the formation of active metabolites (if formed), and/or (6) reduce the production of harmful metabolites in specific tissues and/or produce more effective drugs under combination therapy and/or Or a safer drug, whether or not the combination is intentionally used 152269.doc 201121958 The replacement of an atom with one of its isotopes often causes a change in the rate of reaction of the chemical reaction. This phenomenon is called the kinetic isotope effect (r ΚΙΕ). For example, if the C-H bond breaks during the rate determining step in the chemical reaction (i.e., the step with the highest transition state energy), replacing the hydrogen with deuterium will cause the reaction rate to decrease and the process to slow down. This phenomenon is called the kinetic isotope effect ("DKIE"). See, for example, Foster et al., 1985, 14: 1-36; Kushner et al., CW 知 知. / Pharmacol·, 1999, ΊΊ·. The magnitude of DKIE can be expressed as the ratio of the rate at which the C-Η bond cleaves to the same reaction as the hydrazine-substituted hydrogen. DKIE can range from about 1 (no isotope effect) to very large numbers (such as 50 or more), meaning that when the hydrazine is substituted for hydrogen, the reaction rate can be 1/50 or 1/5 》. The value of 1 can be caused in part by a phenomenon called tunneling, which is the result of the uncertainty principle. The tunneling system is attributed to the small mass of the hydrogen atoms and can sometimes occur due to the transition state involving protons in the absence of the desired activation energy. Because the mass of the atmosphere is greater than hydrogen', the probability of statistically experiencing this phenomenon is much lower.氚(τ) is a radioisotope of hydrogen used in research, fusion reactor neutron generators, and radiopharmaceuticals. The gas is a hydrogen atom having two neutrons in the nucleus and an atomic weight close to three. It occurs naturally at very low concentrations in the environment and is most commonly found in the form of D. The gas decays slowly (half-life 12.3 years) and emits low-energy p-particles that cannot penetrate the outer layers of human skin. Intracorporeal exposure is a major hazard associated with this isotope, however it must be taken in large quantities to pose significant health risks. Compared to cockroaches, the meager amount of 152269.doc 201121958 must be exhausted. The substitution of hydrazine ("τ") for hydrogen produces a stronger bond than hydrazine and gives a numerically larger isotope effect. Similarly, isotopes are substituted for other elements including, but not limited to, 13C or 14c substituted carbon, 33S, 34S or 36S substituted for sulfur, "N substituted nitrogen, and 17〇 or 18〇 substituted oxygen, k for similar kinetics Isotope effect. For example, 'the use of DKIE reduces the hepatotoxicity of fluorosis by presumably limiting the production of reactive substances such as trifluoroethylene chloride. However, this method may not be applicable to all drug classes. For example, Incorporation of hydrazine can cause metabolic switching. The concept of metabolic switching claims that xenogens can be transiently bound and recombined in various configurations prior to chemical reactions (such as oxidation) when phase I enzymatically chelate. The relatively large size of the binding phase of the phase I enzyme is supported by the confounding nature of many metabolic reactions. Metabolic conversion can potentially produce different proportions of known metabolites as well as completely new metabolites. This new metabolite pattern can be given more or more Or less toxic. Animals exhibit various enzymes for the purpose of eliminating foreign substances (such as therapeutic agents) from their circulatory system. Examples of such enzymes include cytochrome p45 Chymase ("CYP"), esterase, protease, reductase, dehydrogenase, and monoamine oxidase react with such foreign substances and convert them into more polar intermediates or metabolites for excretion of the kidneys. Some of the most common pharmaceutical compound metabolic reactions involve the oxidation of carbon-hydrogen (C-H) bonds to carbon-oxygen (c_〇) or carbon-carbon (c_c) 7r bonds. The resulting metabolites may be stable or unstable under physiological conditions and may have substantially different pharmacokinetic, pharmacodynamic, and short-term and long-term toxicities relative to the parent compound. For many drugs, these oxidations are rapid. Therefore, these drugs often require multiple doses or high doses of sputum 152269.doc -10· 201121958 Therefore, isotope enrichment at specific positions of the compounds provided herein will result in similar compounds with natural isotopic compositions. The detectable KIE will affect the pharmacokinetic, pharmacological and/or toxicological profile of the compounds provided herein. [Embodiment] Provided herein are methods for treating or preventing hepatitis C infection in an individual in need thereof, and pharmaceutical compositions and agents suitable for use in such methods. These methods and compositions are described in detail in the following sections. Definitions S When referring to a compound provided herein, the following terms have the following meanings unless otherwise indicated. Unless otherwise defined in (4), all technical and scientific terms used herein have the same meaning as commonly understood by the skilled artisan. In the event that there are multiple definitions of a term in this document, the definitions in this section prevail unless otherwise stated. "Pharmaceutically acceptable salt" includes any salt of a compound provided herein which retains the biological properties of the compound and is non-toxic or otherwise unfavorable for medical use. Such salts can be derived from a wide variety of organic and inorganic counterions well known in the art. Such salts include: (1) acid addition salts with organic or inorganic acids such as hydrochloric acid, hydrogen acid, sulfuric acid, nitric acid, acid, amino acid, acetic acid, trifluoroacetic acid, trigas Acetic acid, propionic acid, caproic acid, cyclopentylpropionic acid, glycolic acid, glutaric acid, pyruvic acid 'lactate, propionic acid, butyric acid, mountain renter 13-san 4 acid, ascorbic acid, malic acid, cis Butyric acid, antibutanic acid, tartaric acid, citric acid, benzoic acid, 3-(4_ by 152269.doc •11·201121958 benzylidene) benzene f acid, picric acid, cinnamic acid, mandelic acid , phthalic acid, lauric acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2· Naphthalenesulfonic acid, 4-toluenesulfonic acid, camphoric acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptanoic acid, 3-phenylpropionic acid , trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, benzoic acid, threonine, hydroxynaphthoic acid, salicylic acid, stearic acid, cyclohexylaminosulfonic acid, quinic acid (quinic) Acid), muconic acid (mucon Ic acid) and its analogous acid; or (2) a salt formed when the acidic proton present in the parent compound satisfies the following: (subsequent substitution: metal ion (eg alkali metal ion, alkaline earth ion or aluminum ion), Or alkali metal or alkaline earth metal hydroxides (such as sodium, potassium, calcium, town, aluminum, lithium, zinc and barium hydroxide), ammonia, or with organic bases, such as aliphatic, alicyclic Group or aromatic organic amines such as ammonia, methylamine, dimethylamine, diethylamine, picoline, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, ornithine, gall Alkali, N, N, _ bicienyl ethylenediamine, chloroprocaine (chl〇r〇pr〇caine), diethanolamine, procaine, N-phenylmercaptophenethylamine, N-mercapto Glucosamine piperazine, cis (hydroxymethyl)-amino decane, tetradecyl ammonium hydroxide and the like. The salt further includes, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraoxane a base ammonium and its analogs, and when the compound contains a basic functional group, includes a non-toxic organic acid or a salt of an inorganic acid, such as a hydrogen halide, For example, hydrochloride and hydrobromide, sulfate, phosphate, amine sulfonate, nitrate, acetate, trifluoroacetate, trichloroacetate, propionate, hexanoate, cyclopentyl Acid salt, & acetate, glutarate, pyruvate, lactate 'C2 152269.doc -12· 201121958 acid salt, succinate, sorbate, ascorbate, malate, cis Oleate, fumarate, tartrate, citrate, benzoate, 3-(4-hydroxybenzhydryl)benzoate, picrate, cinnamate, almond Acid salt, o-diformate, laurate, decane sulfonate, ethane sulfonate, 1,2-ethane-disulfonate, 2-hydroxyethane Acid salt, benzenesulfonate/besylate, 4-gasbenzenesulfonate, 2-naphthalenesulfonate, 4-nonylbenzenesulfonate, camphorate, camphoroate, 4-methyldi Cyclo [2.2.2]-oct-2-ene-1-decanoate, glucoheptanoate, 3-phenylpropionate, trimethylacetate, tert-butyl acetate, lauryl sulfate , gluconate, benzoate, glutamate, Yue naphthalene, salicylate, stearate, cyclohexyl amine salts, salts of quinic acid, muconic acid and the like salts. As used herein, the term "host" includes any single or multicellular organism that can replicate a virus' including cell strains and animals, and is preferably human. Alternatively, the host may carry a portion of the flavivirus genome whose replication or function may be altered by the compounds provided herein. The term host specifically includes infected cells, cells and animals transfected with all or part of the flavivirus genome, especially primates (including chimpanzees) and humans. In most animal applications, the victim is a human patient. However, veterinary applications (such as black capture) in specific indications are explicitly contemplated herein. As used herein, the terms "individual" and "patient" are used interchangeably herein to mean an animal, such as a mammal, including a non-primate (eg, cow, pig, horse, miscellaneous, dog, Rats and mice) and primates (such as wolves 'such as stone crabs wolf m〇n (four)), I52269.doc • 13-201121958 black gorillas and humans) 'and humans, for example. In one embodiment, the individual is refractory or does not respond to current treatment for hepatitis C infection. In another embodiment, the individual is a farm animal (e.g., a horse, cow, pig, etc.) or a pet (e.g., a dog or cat). In one embodiment, the individual is a human. As used herein, IC50 refers to the amount or concentration of a particular test compound that achieves 50% inhibition of the reaction in a test that measures the maximum response. As used herein, EC5G# refers to a dose, concentration or amount of a 50% initiator-dependent reaction of a particular test compound with a maximum performance of a particular reaction induced, stimulated or potentiated by the particular test compound. As used herein, the term "therapeutic agent" refers to any agent that can be used to treat or prevent a condition or its symptoms. In certain embodiments, a π therapeutic agent includes the compounds provided herein. In an embodiment,

Therapeutic agents are agents known to be useful, 戎ρ田Μ + α A times that have been or are currently being used to treat or prevent a condition or one or more of its symptoms. As used herein, the terms "individual" and "patient" are used interchangeably herein. The term "individual" refers to an animal, preferably a mammal, including non-primates (eg, cows, pigs, horses, I vaccines, dogs, rats, and mice) and primates (eg, monkeys). Such as stone crab, wolf, black and human), and better for humans. In one embodiment, the individual is refractory or does not respond to current treatment for hepatitis C infection. In another embodiment, the individual is a farmer such as a horse, cow, pig, etc.) or a pet (such as a dog or cat). In a preferred embodiment, the individual is a human. The term "therapeutic agent" as used herein refers to any agent that can be used to treat, manage, or ameliorate a condition or one or more symptoms thereof. In certain embodiments 152269.doc 201121958, the term "therapeutic agent" refers to a compound provided herein. In certain other embodiments, the term "therapeutic agent" does not refer to a compound provided herein. The therapeutic agent is preferably an agent known to be suitable for use in or for the treatment, management, prevention or amelioration of a condition or one or more of its symptoms. As used herein, "therapeutically effective amount" means that a compound or complex or composition is sufficient to effect treatment of the disease when administered to an individual to treat the disease. The "therapeutically effective amount" may vary depending on the compound, the disease and its severity, and the age, weight, etc. of the individual to be treated. As used herein, "treating" any disease or condition refers to amelioration of a disease or condition present in an individual. In another embodiment, 'the treatment j refers to at least one physical parameter that may be indistinguishable to the individual. In the embodiment - 'treatment' means either physically (eg, stabilizing the discernible symptoms) or in the physiology Academically (eg, stabilizing physical parameters) or modulating a disease or condition on both. In yet another embodiment, "treatment" refers to delaying the onset of a disease or condition. As used herein, "preventive agent as used herein" refers to any agent that can be used to prevent a condition or one or more of them; and to remedy the symptoms of #夕&&& Αι 尺 彳 U. In certain embodiments, the term "preventing agent" refers to a compound that is provided herein as a fork. In certain other embodiments, the term "preventing agent" does not refer to a compound that has been captured. The prophylactic agent is preferably an agent known to be suitable for, or has been used in, or used to prevent or impair the onset, progression, progression and/or severity of the condition. As used herein, the term 'pre-" is used to mean a combination of a therapy (eg, a prophylactic or therapeutic agent) or a combination of a therapeutic therapy, such as a prophylactic or therapeutic sword, and (d) Recurrence, onset of symptoms of a therapeutic agent or development of 152269.doc -15- 201121958. As used herein, the phrase "prophylactically effective amount" means that the therapy (eg, a prophylactic agent) is sufficient to prevent the development, recurrence, or onset of one or more symptoms associated with the condition (or to enhance or modify another therapy (eg, another The amount of a preventive agent). "Important, isotope composition" means the amount of each isotope for a given atom. "Natural isotopic composition" means the isotopic composition or abundance of the atom; Atom containing a natural isotope (6) 2 may also be referred to herein as an "unenriched" atom. Unless otherwise specified, the atom of the compound described herein means the (four) stability of the atom. For example, unless otherwise stated, when a person is considered to be "Η" or "hydrogen", it should be understood that the position is composed of hydrogen with its natural cyclin composition. 2 = used, "isotopic enrichment" refers to the isotope of an atom (4): the natural isotopic composition of the atom. "Isotopic enrichment" can also mean that the oral substance contains at least _ atoms of isotopic composition. Ding 炙 natural 冋 冋 「 ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” Take two: the ratio, instead of the natural atom of the atom, the 1% increase in the position in the established sample means that the knife contains 氘 at the specified position. Therefore, the distribution of the compound which is about 〇〇 is synthesized at any position t: two in = no increase in the starting material, and the claw enrichment at the 17th position is about 0.0156%. The isotope enrichment of the ' and D' can be determined by a known method (including mass spectrometry and nuclear magnetic resonance spectroscopy) known to those skilled in the art. 152269.doc • 16 - 201121958. The terms 'alkyl, alkoxy, carbonyl, and the like, as used herein, are generally understood to be used as understood by those skilled in the art. As used herein, if an "alkyl" carbon chain is not specified, it contains from 1 to 20 carbons, from 1 to 16 carbons or from 1 to 6 carbons, and is linear, branched or cyclic. The cyclic alkyl group includes a cycloalkyl carbon chain as defined herein, or a portion of a chain-burning carbon chain such as methylene cyclopropane or methylene cyclobutane. In some embodiments, the burnt carbon bond contains from 1 to 6 carbons. Exemplary alkyl groups herein include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl 'n-butyl, second butyl, tert-butyl, isopentyl, neopentyl Base, third amyl, isohexyl. As used herein, lower alkyl means that the carbon chain has from about 1 carbon to about 6 carbons. As used herein, if a "mercapto" carbon chain is not specified, it contains 2 to 20 carbons, 2 to 16 carbons or 2 to 6 carbon's and is a straight or branched chain. In certain embodiments the 'alkenyl carbon chain contains from 2 to 6 carbons. The dilute carbon chain of 2 to 20 carbons has 1 to 8 double bonds in some embodiments, and the alkenyl carbon chain of 2 to 16 carbons has 1 to 5 double bonds in some embodiments. The dilute carbon chain of 2 to 6 carbons has 1 to 2 double bonds in some embodiments. Exemplary alkenyl groups herein include, but are not limited to, ethylene, 1-propenyl, 2-propenyl, isopropenyl, 1-butyryl, 2-butadienyl, 3-butadienyl, I, 3, butadienyl. As used herein, low carbon dilute refers to a carbon chain having from about 2 carbons to about 6 carbons. As used herein, if an "alkynyl" carbon chain is not specified, it contains 2 to 20 carbons, 2 to 16 carbons, or 2 to 6 carbons, and is a straight or branched bond. In some embodiments, 152269.doc -17- 201121958 'blocky carbon chains contain 2 to 6 carbons. The 2 to 2 carbon block carbon bond contains (1) a bond in some embodiments, and the (1) carbon bond has a (1) bond in some embodiments. (1) Blocks of carbon The base carbon bond contains (1) a bond in some embodiments. Exemplary alkynyl groups herein include, but are not limited to, ethynyl, propynyl and decynyl. As used herein, a lower alkynyl refers to a carbon chain having from about 2 carbons to about 6 carbons. As used herein, "aryl" refers to an aromatic monocyclic or polycyclic group containing from 6 to 9 carbon atoms. Aryl groups include, but are not limited to, groups such as a benzyl group, a substituted group, a phenyl group, a substituted phenyl group, a naphthyl group, and a substituted naphthyl group. As used herein, "ring-house" refers to a saturated monocyclic or polycyclic ring having from 3 to 3/5 carbon atoms in some embodiments, and having from 3 to 6 carbon atoms in other embodiments; The sulfhydryl group and the ring block group refer to a monocyclic or polycyclic ring system comprising at least one double bond and at least one reference bond, respectively. The cycloaliphatic and cyclosalradyl groups may contain from 3 to 10 carbon atoms in certain embodiments, wherein the cycloaliphatic group contains from 4 to 7 carbon atoms in other embodiments, and the cycloalkynyl group in other embodiments contains 8 Up to 10 carbon atoms. The cycloalkyl, cycloalkenyl and cycloalkynyl ring system may be composed of one ring or two or more rings which may be fused, bridged or screwed together. As used herein, "# base", "dentate" or "_子" means F' CM, Br or I. As used herein, "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms have been replaced by a halogen. "Lower carbon tooth alkyl" means a lower alkyl group in which one or more hydrogen atoms are replaced by a hydroxyl group. Such groups include, but are not limited to, chloromethyl, trifluoromethyl and 1-chloro-2-fluoroethyl. 152269.doc -18· 201121958 As used herein, "arylalkyl" refers to an aryl group bonded to an alkyl group. The point of attachment of the arylalkyl group can be through an aryl or alkyl moiety. Such groups include, but are not limited to, the fluorenyl (i.e., phenylmethyl), phenylethyl, and fluorenylmethyl- phenylethyl. As used herein, "mercapto" refers to the group _c(〇)R, wherein R is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, hetero Aryl, heteroarylalkyl, as defined herein. Representative examples include, but are not limited to, methionyl 'ethenyl, cyclohexylcarbonyl, cyclohexyldecylcarbonyl, benzhydryl, stupinylcarbonyl, and the like. As used herein, "alkoxy" refers to the group _〇R, wherein R is alkyl. Specific alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, second butoxy, n-pentyloxy, n-hexyloxy, 1,2-dimethylbutoxy and the like. As used herein, "alkoxycarbonyl" refers to the group _c(〇)alkoxy, wherein the alkoxy group is as defined herein. As used herein, "amino group" refers to the group νη2. As used herein, "alkylamino" refers to the group alkyl-NR, wherein R. is selected from the group consisting of hydrogen and alkyl. As used herein, "dialkylamino" means a group _nrr, wherein 艮 and R independently represent alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted ring. Alkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl or substituted heteroaryl, as defined herein. As used herein, "carboxy" refers to a group {(OWH. As used herein, "radio" refers to the group _〇H. 152269.doc -19· 201121958 as used herein, "nitro" Refers to a group _N〇2. As used herein, "cyano" refers to the group -CN. As used herein, "solvate" refers to a compound provided herein or a salt thereof, which further includes chemistry A metered or non-stoichiometric amount of a solvent that is combined by a non-covalent intermolecular force. 赍 This sword, ^ 吐田, when the mixture is water, the solvate is a hydrate. It should be understood that the same molecular formula, but the atomic bond Compounds with different knot properties or sequences or different arrangement of atoms are called "isomers." Isomers with different arrangement of atoms in space are called "stereoisomers. The stereoisomers that are not mirror images of each other are called "diastereomers". Stereoisomers that are "reflective" and non-superimposable mirror images of each other are termed "enantiomers." When a compound has an asymmetric center, such as when it is bonded to four different groups, a pair may exist. Enantiomers. The enantiomers can be asymmetric Absolute configuration of the heart and characterized according to the Cahn and Prel〇g of rules (Cahn et al., 1966, hgew 78:. 413-447, dwgew.

Chem., Int. Ed. Engl. 5:385-414 : Angew. Chem., Int. Five sighs / 5:511) ; Prelog &Helmchen, 1982,J«gew.C/zew. 94:614-631 , Angew. Chem. Internat. Ed. Eng. 21:567-583 ; Mata and Lobo, 1993, reira/zei/row.· 4:657-668) Designated as (7?) or (S)' or may be borrowed Characterized by the way the molecule rotates the plane of polarized light and designated as right-handed or left-handed (ie, (+). isomer or (-)-isomer, respectively). The palm compounds may be present as individual enantiomers or as a mixture thereof. A mixture containing equal proportions of the enantiomers is referred to as a "racemic mixture." 152269.doc • 20· 201121958 In certain embodiments, the compounds provided herein may have one or more asymmetric centers, such compounds may thus be individual (R)- or (s)-enantiomers or Made in the form of a mixture. Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include the individual enantiomers and mixtures thereof (racemic mixtures or other mixtures), for example, by stereochemistry at any position of the formula. The method of determining stereochemistry and isolating stereoisomers is well known in the art. In a particular embodiment, the stereoisomeric system of the compounds described herein is formed after treatment with a base. In certain embodiments, the compounds provided herein are "stereochemically pure." Those skilled in the art will recognize that stereochemically pure compounds or compounds having a level of stereochemical purity are "pure". Of course, this level of purity will be less than 100%. In certain embodiments, "stereochemically pure" designates a compound that is substantially free of alternations. In a particular embodiment, the compound is 85 〇/〇, 90%, 91%, 92% '93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% free Other isomers. As used herein, the term "label" means a written, printed or graphic document displayed on an immediate container of an article, such as a written material displayed on a vial containing a pharmaceutically active agent. As used herein, the term "labeling" means all marks and other written, printed or graphic documents on or associated with any item or any container or covering material thereof, such as accompanying or accompanying medicine. A drug label or instructional videotape or Dvd for the container of the active agent. HCV treatment 152269.doc -21 - 201121958 It has been surprisingly discovered that a small group of P38 MAP kinase inhibitors are potent 11 (: sputum entry inhibitors. Not limited to a specific mechanism of action, the compounds provided herein can be docked with SR-B1 (involving HCV) The host hepatocyte cell membrane protein, which enters the host, interacts to inhibit HCV entry into the host cell. Thus, provided herein are HCV entry inhibitors and pharmaceutical compositions thereof, which are useful for treating or preventing HCV infection in an individual in need thereof. The methods of topical therapy are described in detail in the following sections. Compounds can be any of the compounds provided herein, as described in the following article section. In certain embodiments, the compounds are in the form of a pharmaceutical composition or dosage form, as described in the following article section. As mentioned above, the current HCV therapy is co-administered with interferon and ribavirin. The current therapy is operated by regulating the immune system of the individual to treat or prevent HCV infection. The compounds are manipulated by novel mechanisms. , compositions and methods provide a novel therapy for treating or preventing HCV infection. Therefore, it can be beneficial for infecting HCV or feeling Any individual in the risk of HCV, and in particular an individual who is not responsive to current therapies. In certain embodiments, the individual may be any individual infected with or at risk of contracting HCV. The risk of infection or infection may be Any person skilled in the art will recognize any suitable technique for determining. Particularly preferred individuals are humans infected with HCV. HC V can be any hcV known to those skilled in the art. At least 6 HCV genotypes are currently known to those skilled in the art. And at least 50 HCV subtypes. HCV can be any genotype or subtype known to those skilled in the art. In certain embodiments, HCV is a genotype or subtype that is not yet characterized. In certain embodiments The system infects a single genotype of HCV. In certain embodiments 152269.doc • 22-201121958, the 'system affects HCV of multiple subtypes or multiple genotypes. In certain embodiments, HCV is genotype 1 and May be any subtype. For example, in certain embodiments, HCV infection with HCV subtype la, 115 or lc^sense genotype 1 is poorly responsive to current interferon therapy. In certain embodiments This article provides The method facilitates the therapy of Hcv infection of genotype 1. In certain embodiments, HCV is not genotype. In certain embodiments, HCV is genotype 2 and can be any subtype. For example, in In certain embodiments, HCV is subtype 2a, 2b or 2c. In certain embodiments, HCV is genotype 3 and can be of any subtype. For example, in certain embodiments, HCV is Subtype 3a, 3b or l〇a. In certain embodiments, HCV is genotype 4 and can be of any subtype. For example, in certain embodiments, HCV is subtype 4a. In some embodiments In the example, Hcv is genotype 5 and can be any subtype. For example, in certain embodiments, the HCV is subtype 5a. In certain embodiments, the HCV is genotype 6 and can be of any subtype. By way of example, a 'in certain embodiments, Hcv is subtype 6a, 6b, 7b, 8b, 9a or Ua. See, for example, the melon claw (10) heart, 2〇〇4, j仏”~夂85:3 173-88; Simmonds, 2001, j. Gen^? 82? 693„ 712, the inner valley is quoted in full by Into this article. In certain embodiments, the individual has never received a therapy or prevention of HCV infection. In other embodiments, the individual has previously received therapy or prevention of HCV infection as an example. In some embodiments, the individual has not responded to the therapy. In fact, under current interferon therapy, up to 5 (four) or more HCV individuals Do not respond to the therapy. In certain embodiments, the individual may be 152269.doc • 23· 201121958 Individuals who receive therapy but continue to develop a viral infection or one or more symptoms thereof. In certain embodiments, the individual may be receiving therapy but failing to achieve An individual with a persistent virological response. In certain embodiments, an individual who has received a therapy for HCV infection but has failed has shown a decrease in HCV RNA content of 2 logiG after 12 weeks of therapy. Salty 彳 § § § § § § § § § § § § § § § § § § § § § § § § § § § § § § § § § § § § Because the compounds provided herein act by a different mechanism than current HCV therapies, it is believed that the compounds provided herein should be effective in treating such non-responders. In certain embodiments, the individual is an individual who discontinues HCV therapy due to one or more adverse events associated with the therapy. In certain embodiments, the individual is an individual who does not qualify for the current therapy. For example, certain therapies for HCV are associated with neuropsychiatric events. Interferon (IFN)-a plus ribavirin is associated with a high rate of depression. Depressive symptoms have been associated with poorer outcomes in a number of medical conditions. During HCV therapy, life-threatening or fatal neuropsychiatric events have occurred in individuals with and without psychiatric conditions, including suicide, suicide, and homicide , depression, drug addiction / overdose recurrence and aggressive behavior. Especially for individuals with psychiatric disorders, interferon-induced depression limits the treatment of chronic hepatitis C. Psychiatric side effects are currently common for interferon therapy and cause approximately 1% to 2% of current HCV infection therapy to be discontinued.

Thus, the present invention provides methods for treating or preventing HCV infection in individuals who are contraindicated in the treatment of current HCV therapy, such as the risk of neuropsychiatric events such as depression. In some embodiments, provided herein are methods of treating or preventing hcv infection in an individual treated with current HCV 152269.doc _24·201121958 = in a neuropsychiatric event (such as a gynecological condition) or a risk indicator thereof. In the context of the present invention, there is provided a method of treating HCV infection in a neuropsychiatric event (such as a camping disorder) or an individual whose risk indicates a reduction in the current dose of HCV therapy. ‘, ^ 目刖 Therapy is also contraindicated in individuals who are allergic to interferon or ribavirin or both, or any other component that is administered to interferon or any other component of the drug. Current therapies are not suitable for individuals with hemoglobin (e.g., thalassemia maj〇r, sickle cell anemia) and other individuals at risk of hematological side effects of current therapies. Common hematological side effects include myelosuppression, spastic neutropenia, and thrombocytopenia. Furthermore, 'virus (4) red blood cells are toxic and related to hemolysis. Therefore, the present invention provides individuals in individuals who are allergic to interferon or ribavirin or both, such as individuals with serotoninemia and individuals with sickle cell anemia, and are currently in therapy. A method of treating or preventing HCV infection in other individuals at risk of hematological side effects. In certain embodiments, the individual has received HCV therapy and discontinued the therapy prior to administration of the methods provided herein. In other embodiments, the individual has received therapy and continues to receive the therapy and to administer the methods provided herein. The methods herein can be co-administered with other HCV therapies based on the judgment of those skilled in the art. In some embodiments, the methods or compositions provided herein can be co-administered with a reduced dose of other HCV therapies. In certain embodiments, a compound of Formula I provided herein is co-administered with an antiviral agent selected from the group consisting of a nucleoside polymerase inhibitor, a non-nucleoside polymerase inhibitor, a protease inhibitor, a cyclophilin Regulator, interferon 152269.doc •25· 201121958 and disease Qin sniffing. In one embodiment, in one embodiment, in another embodiment, the method of the body is applied in some embodiments. For example, a compound selected from the group consisting of interferon, interferon, and interferon alpha plus disease i is administered together with interferon. The compound of formula I is administered with ribavirin. The compound of formula I is associated with interferon and ribavirin. This article provides treatment for the treatment of refractory interferon. In some embodiments, the individual can be an individual who is refractory to treatment with or - a plurality of agents selected from the group consisting of interferon, interferon «, pegylated interferon alpha, interferon plus viral sputum, interference A-alpha plus virus 11 sits and pegylated interferon alpha plus viral saliva. In other embodiments, because current therapies are also contraindicated in pregnant women, the present invention provides methods of treating hcv infection in an individual who is pregnant or likely to become pregnant. μ In certain embodiments, the individual has been infected with (c〇_infecU〇n) Hcv and mv, or at risk of co-infection with HCV and HIV. For example, in the United States, 30% of HIV individuals are co-infected with Hcv and evidence suggests that people infected with HIV have a much faster process of hepatitis C infection. Maier & Wu, 2〇〇2, ❿J 8:577-57. The methods provided herein can be used to treat or prevent HCV infection in such individuals. The elimination of HCV in these individuals will reduce the mortality caused by end-stage liver disease. In the case of ou 152269.doc -26- 201121958 AIDS-deficient immunodeficiency, the risk of developing liver disease is higher than that of individuals without severe AIDS-deficient immunodeficiency. See, for example, Lesens et al., 1999, //«/eci Db 179: 1254-1258. In certain embodiments 'administering a method or composition provided herein after liver transplantation^ in the United States 'Hepatitis C is the leading cause of liver transplantation' and many individuals undergoing liver transplantation are still HCV positive after transplantation . Thus, the present invention provides methods of treating such recurrent HCV subjects with the compounds or compositions provided herein. In certain embodiments, the individual is treated according to the methods provided herein to prevent recurrent HCV infection during, during, or after liver transplantation. Compounds Provided herein are therapeutic or prophylactic treatments in a subject by administering to a subject in need thereof an effective amount of a ketoguanamine compound of the following formula (1) or (II) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof; Method of hepatitis C infection:

R is (1:1-〇8 alkyl; C5-C8 cycloalkyl or c7-Ci〇 aryl; 152269.doc -27· 201121958 R3 is hydrogen, cyano, -CONHR6, -NHS02R7 or -S02N (R8)2; R is C丨-c4 alkyl; R is 匚"(:4 alkoxy or -N(R8)2; R6 is 2-pyridyl or Ci_C6 alkyl, wherein one or more carbon atoms If necessary, it is replaced by an oxygen atom; R7 is a Ci-C4 alkyl group, a CH2CF3 group, a phenylhydrazine group or a phenyl group; and R is a CVC4 alkyl group; r9 is a desert or a 6-(amidinopyridinyl-3-yl group;

Rl° is hydrogen or -CONHR"; and R" is hydrogen or CVC4 alkyl; the restriction is that if r3 is shed 2RW is methyl, then Ri is not methyl; the restriction is that if R10 is hydrogen, 9 L is 6-(Methylamino)pyridin-3-yl; and the restriction is that if RH is cyclopropene*, then R9 is bromine. In one embodiment, the other restriction bars are -nHS〇2r9. f is the right R is a methyl group, then r3 is not in another embodiment, the 苴 is limited to the a a, 9 is if R2 is methyl and R3 is -NHS 〇 2r9, then the rule 9 is not A base. Nhso2r9, in the second embodiment, the other restriction condition is _ then R2 is not a methyl group. . If R3 is -NHS02R9 and in another embodiment, the other restriction is that R is methyl, then R2 is not methyl. Ethyl, isopropyl or in some embodiments 'r, is, 152269.doc -28-^0 201121958 In one embodiment, R1 is methyl, / or, in one embodiment, R丨 is isopropyl or hydrazine. lQH In one embodiment, R 1 is . Benzene In some embodiments, R2a is a horse, a second butyl group, a hexyl group or a 1-methylethyl group. In some embodiments, R2 is a third butyl group. In some embodiments, R3 is hydrogen. In some embodiments, R3 is -NHS〇2RlR, methyl. In the second embodiment, if R2 is a methyl group, R3 is not -nhso2r9. In one embodiment, if R2 is methyl mN 2R9, then r is not methyl in another embodiment. If R3 is ·nhs〇2R9, then R2 is not a sulfhydryl group. If R3 is -nhso2r9 and V is a methyl group, then r2 is in some embodiments, and r4 is a third butyl group. In one embodiment, R5 is methoxy or dimethylamino. In some embodiments, 'r6 is methyl, ethyl, propyl, benzyl, methylenecyclopropyl or 2' ratio. Alkyl. In an embodiment, R7 is methyl or B. In one embodiment, each R8 is a methyl group. In: a: order, R, methyl or ethyl. In an embodiment, the ruler 9 is a 6•(methylamino) bite. _3_基。 In one embodiment, R9 is bromine; R10 is -CONHRn; and ruler 11 is 152269.doc •29·201121958 C]-C4 alkyl. And R11 is in one embodiment, R9 is bromine; R10 is -CONHR11; C1-C4 alkyl. The salt has, in one embodiment, a compound or a pharmaceutically acceptable formula:

〇, 〇 In one embodiment, the compound or a pharmaceutically acceptable salt thereof has the formula:

The salt of P ο has, in one embodiment, a compound or a pharmaceutically acceptable formula:

0. In one embodiment, the compound or a pharmaceutically acceptable salt thereof has the formula: — 152269.doc -30- 201121958

In one embodiment, the compound or its pharmaceutically acceptable formula is as follows:

In one embodiment: the compound or a pharmaceutically acceptable salt thereof has

The compound or a pharmaceutically acceptable salt thereof has, in one embodiment:

In one embodiment the compound or a pharmaceutically acceptable salt thereof has 152269.doc • 31 · 201121958 Formula: η3 (〇 In one embodiment: the following formula: In one embodiment: the following formula: h3c.〇/v ^,n In one embodiment, the following formula: ΗCrKi

a compound or a pharmaceutically acceptable salt thereof

a compound or a pharmaceutically acceptable salt thereof

a compound or a pharmaceutically acceptable salt thereof

152269.doc • 32- 201121958 In one embodiment, the compound or a pharmaceutically acceptable salt thereof has the formula:

In one embodiment, the compound or a pharmaceutically acceptable salt thereof has the formula:

In one embodiment, the compound or a pharmaceutically acceptable salt thereof has the formula:

In one embodiment, the compound or a pharmaceutically acceptable salt thereof has the formula:

152269.doc -33- 201121958 In one embodiment, the compound or a pharmaceutically acceptable salt thereof has the formula:

In one embodiment, the compound or a pharmaceutically acceptable salt thereof has the formula:

In one embodiment: the compound or a pharmaceutically acceptable salt thereof has

In one embodiment: the compound or a pharmaceutically acceptable salt thereof has 152269.doc -34- 201121958

In one embodiment, the compound or a pharmaceutically acceptable salt thereof has the formula:

In one embodiment, the compound or a pharmaceutically acceptable salt thereof has the formula:

In one embodiment, the compound or a pharmaceutically acceptable salt thereof has the formula:

152269.doc -35- 201121958 In one embodiment, the compound or a pharmaceutically acceptable salt thereof has the formula:

In one embodiment, the compound or a pharmaceutically acceptable salt thereof has the formula:

Certain of the compounds provided herein have been previously disclosed in U.S. Patent Publication No. 2005/0107399, the disclosure of which is incorporated herein in its entirety. U.S. Patent Publication No. 2005/0107399 does not disclose the treatment of HCV with an entry inhibitor. U.S. Patent Publication No. 2005/01 07399 does not identify or select the specific compounds provided herein for the treatment of HCV. Preparation of Compounds The compounds provided herein can be prepared, isolated or obtained by any method known to those skilled in the art. An exemplary method of preparing a compound of the formula is provided below. 152269.doc -36 - 201121958 Process A ·

Process B:

R4 Ο

RS Ο

(I) The compound of formula 1 can be prepared according to the general procedure described above and hydrazine. The preparation of specific intermediates in the compounds of formula I can be prepared as follows. The following schemes are only preparative! An exemplary method of the compound, not intended to be local. Those skilled in the art understand that there are alternative methods of preparing compounds of formula I in accordance with methods known in the art. Synthesis of Tsaiki·_based-acetic acid derivatives··

4-[2.(Naphthyloxy)-ethyl]-morpholine can be prepared, for example, by reacting 2·hydroxynaphthalene with 152269.doc •37-201121958 2-oxoethylmorpholine in the presence of a base. .

X = och3, oh, Cl

Treatment of 4-[2-(naphthalen-1-yloxy)-ethyl]-morphine with chloroglyoxylate in the presence of A1C13 provides 4-[2-(norpoline-4-yl-ethoxy) -Tea-1-yl)-branched-yl acetate or ethyl ester' which can react with a hydroxide base to provide the corresponding carboxylic acid, or can react with HCl to provide the corresponding carboxylic acid, and subsequently with ethylene The chlorine reacts to produce the corresponding acid gasification. This specific derivative of the indol-1-yl-indenyl-acetic acid derivative can be further reacted with a substituted aniline or a 3-amino-thiophene to provide a compound. Exemplary substituted aniline intermediates:

The above-mentioned aniline compound substituted by 152269.doc •38·201121958 can be prepared by a commercially available reagent by a method known in the art. For example, 5_t-butyl-2-yloxy-indole, 3-phenylenediamine is available from Sigma-Aldrich Corp. (St. Louis, MO), 5-tert-butyl-2-methoxy The base acid is available from Chemos GmbH (Regenstauf, Germany) and 4-tert-butyl benzoate is available from Acr〇S 〇rganics (ThermoFisher Scientific Inc., Waltham, ΜΑ). The substituted aniline intermediate can then be used as provided in the scheme to give the above formula. An exemplary 3-amino-thiophene intermediate:

The substituted 3-amino-η pheno compound described above is either commercially available or can be prepared by commercially available reagents by methods known in the art. For example, methyl 5-tert-butylthiophene-2-decanoate and 3-tert-butoxycarbonylamino-5-t-butylthiophene-2-decanic acid are commercially available from Fiu〇r〇chem Ud. (Derbyshire, UK) AChemPur GmbH (Karlsruhe, Germany) The intermediate formula can then be obtained using these intermediates as provided in Scheme B. Preparation of N-substituted-5-tert-butyl-2-methoxy_3_(2-(4-methoxynaphthalene)-yl)-2-ketoethylamino)benzamide:

152269.doc •39· 201121958 N-substituted-5-t-butyl-2-methoxy-3-(2-(4-methoxynaphthalene 2-ketoethylamino)benzamide It can be prepared by the general procedure of Scheme a as follows. 5. Third tert-butyl-2-methoxy-3-nitrobenzoic acid is used, for example, from 5 - tert-butyl in the presence of acetic acid. Preparation of 2-nonyloxybenzoic acid. Next, 5·t-butyl-2-methoxy-3-nitobenzoic acid is treated with ethylene dioxane and amine in order to obtain hydrazine _ substituted 5_ third butyl Base 2_曱oxy_3•nitro-benzamide, which can be reduced with Pd/C and Η2 to provide the corresponding Ν-substituted _5_t-butyl-2-methoxy-3-amino group -benzimidamide. Ν-substituted-5-t-butyl-2-methoxy-3-(2-(4-methoxynaphthalene-2-ketoethylamino)benzamide By substituting the ice from the previous step with -5-tert-butyl-2-methoxy-3-indolyl benzoguanamine and 4_[2_(morpholin-4-yl-ethoxy-naphthalene) -1-yl)-keto-ethyl chlorochloride (prepared as described above) is obtained by reaction. & Preparation of a compound of formula (II):

Ν(-)-substituted _5_t-butyl-2- methoxy (methylamino) ° bite-3_yl)-naphthalene·i•yl)·2_cylamine The benzylamine can be prepared by the general procedure of Scheme C as described below. 152269.doc -40· 201121958 Process c:

DCM, room temperature, overnight 0/0 room temperature, 3 hours

As shown above, N-substituted-5-t-butyl-2-decyloxy-3-(2-bromo-naphthalen-1-yl)-2-ketoacetamido) of formula (II) Benzylamine can be prepared according to Scheme C, such as the bromide compound to prepare the above corresponding N-substituted-5-t-butyl-2-methoxy-3-(2-(4-(6-(methylamine)) An intermediate in the product of the product of the formula -3-yl)-na-1 -yl)-2-indanylamino)benzamide. Pharmaceutical salts 152269.doc -41 - 201121958 The compounds provided herein may be in neutral or salt form. The salt form can be any salt form known to those skilled in the art. When the compound provided herein is substituted with a basic moiety, an acid addition salt can be formed. The acid which can be used to prepare the acid addition salt preferably comprises an acid which, when combined with the free base, produces a pharmaceutically acceptable salt (i.e., the anion of the salt is not toxic to the individual in the pharmaceutical dosage of the salt). Pharmaceutically acceptable salts include, but are not limited to, salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, aminosulfonic acid, and nitric acid; and organic acids such as acetic acid, trifluoro Acetic acid, trichloroacetic acid, propionic acid, caproic acid, cyclopentylpropionic acid, glycolic acid, glutaric acid, pyruvic acid, lactic acid, malonic acid, succinic acid, sorbic acid, ascorbic acid, malic acid, maleic acid Acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzyl)benzoic acid, picric acid, cinnamic acid, mandelic acid, phthalic acid, lauric acid, methanesulfonic acid Ethane, ethanesulfonic acid, i, 2, ethane, disulfonic acid, 2-ethylidene-burning acid, benzoic acid, 4-benzoic acid, 2-naphthoic acid, 4-toluenesulfonic acid, camphor Acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]·oct-2-ene·1-carboxylic acid, glucoheptanoic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid , lauryl sulfate, gluconic acid, benzoic acid, facial acid, hydroxynaphthoic acid, salicylic acid, stearic acid, cyclohexylaminosulfonic acid, quinic acid, muconic acid and the like. Corresponding acid addition salts include hydrogen complexes such as hydrochlorides and hydrobromides, sulfates, phosphates, amine sulfonates, nitrates, acetates, trifluoroacetates, trisodium acetates, propionic acid Salt, hexanoate, cyclopentylpropionate, glycolate, glutarate, pyruvate, lactate, malonate, butyl 152269.doc • 42· 201121958 acid salt, sorbate, Ascorbate, malate, maleate, fumarate, tartrate, citrate, benzoate, 3-(4-hydroxybenzhydryl)benzoate, picric acid Salt, cinnamate, mandelate, phthalate, laurate, methanesulfonate (methanesulfonate), ethanesulfonate, hydrazine, 2-ethane-disulfonate, 2-hydroxyethane sulfonate, benzenesulfonate, 4-gasbenzenesulfonate, 2-naphthalenesulfonate, 4-nonylbenzenesulfonate, camphorate, camphorsulfonate, 4-mercapto Bicyclo[2.2.2]-oct-2-ene-1-nonanoate, glucoheptanoate, 3-phenylpropionate, trimethylacetate, tert-butyl acetate, lauryl sulfate Salt 'gluconate, benzoate, Faceted amines, naphthoates, salicylates, stearates, cyclohexylamine sulfonates, quinic acid salts, muconate salts and the like. An acid addition salt of a compound which can be prepared by reacting a free base with a suitable S-text, by applying or adapting a known method. For example, an acid addition salt can be prepared by dissolving a free test in a water or liquid alcohol solution or other suitable solvent containing a suitable acid, and isolating the salt by evaporating the solution; or allowing the free test with an acid in the organic The reaction is carried out in a solvent, in which case the salt is directly isolated or can be obtained by concentrating the solution. The acid addition salts of the compounds provided herein can be regenerated from the salt by the application or adaptation of known methods. For example, t ' can be regenerated from its acid addition salt by treatment with a test such as a carbonated aqueous solution or aqueous ammonia solution. When the compound provided herein is substituted with an acid moiety, an addition salt can be formed. Pharmaceutically acceptable salts (including, for example, soil test metal salts) are derived from the following tests (4): sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium oxide, oxygenated gas, gas oxidation clock, Chlorine oxidation, gas oxidation 152269.doc -43· 201121958 钡, and organic amines, such as aliphatic, alicyclic or aromatic organic amines, such as ammonia, guanamine, monoamine, diethylamine, sulfhydryl Biting, ethanolamine, diethanolamine, diethanolamine, ethylenediamine, lysine arginine, uric acid, choline, N, N,-diphenylmercaptoethylenediamine, gas procaine, diethanolamine , procaine, N-phenylmercaptophenethylamine, N-methylglucamine piperazine, ginseng (hydroxymethyl)-aminomethane, tetramethylammonium hydroxide and the like. The metal salts of the compounds provided herein can be obtained by contacting a hydride, hydroxide, carbonate or similar reactive compound of the selected metal in an aqueous or organic solvent with a compound of the free acid form. The aqueous solvent may be water, or it may be a mixture of water and an organic solvent, preferably an alcohol such as decyl alcohol or ethanol; a ketone such as acetone; an aliphatic ether such as tetrahydrofuran; or an ester such as ethyl acetate ester. These reactions are usually carried out at ambient temperature, but may be carried out under heating if necessary. The amine salts of the compounds provided herein can be obtained by contacting the amine with an aqueous acid or an organic solvent in contact with the free acid form of the compound. Suitable aqueous solvents include water, and mixtures of water with an alcohol such as methanol or ethanol, an ether such as tetrahydrofuran, a nitrile such as acetonitrile, or a ketone such as acetone. Amino acid salts can be prepared analogously. The base addition salt of the compound provided herein can be regenerated from the salt by the application of the "Knowledge 6" method. For example, the parent compound can be regenerated from its base addition salt by treatment with an acid such as hydrochloric acid. Pharmaceutical Compositions and Methods of Administration The compounds used in the methods provided herein can be provided using a pharmaceutical composition comprising at least one compound of formula (1) or a pharmaceutically acceptable salt thereof, 152269.doc • 44 - 201121958, It is used alone or in combination with one or more compatible and pharmaceutically acceptable carriers such as diluents or adjuvants or in combination with another anti-Hcv agent. In clinical practice, the compounds provided herein can be administered by (4) conventional routes, in particular, orally, parenterally, rectally or by inhalation (e.g., in the form of an aerosol). The compounds provided herein are preferably administered orally. Tablets, pills, hard gelatin capsules, powders or granules can be used as a solid composition for oral administration. In such compositions, the active product may be in admixture with a plurality of inert diluents or adjuvants (such as silk, lactose or starch) such compositions may contain materials other than diluents, such as a lubricant such as stearic acid, or A coating intended to control release. It is possible to use a composition such as a moisturizing product or a sweet product which can be used with a composition such as a solution which is acceptable for water or a liquid, such as a solution which is acceptable for water or liquid, or a floating m. Or seasoning products. Buddy for parenteral administration of diol diol, polyethylene glycol, vegetable oil (especially ... I liquid. Can use propylene, such as oleic acid) as "(4) organic S 曰 ( The agent, especially the humectant, the isotonic composition may also contain a plurality of means of emulsifier, dispersant and stabilizer in a plurality of ways. Alternatively, by heating, the bacteria are used, and the radiation is prepared by irradiation. Such aseptic solid compositions: other injectable sterile medium in the form of a non-incorporate composition. dissolved in sterile water or any composition for rectal administration is _ or Zhisheng capsule, in addition to the active ingredient 152269.doc -45· 201121958 also contains excipients, such as 旷J province such as cocoa butter, semi-synthetic glycerides or polyethylene glycol 0. It can also be an aerosol. It is used in the form of liquid aerosol, combination a stable solution, or a solid composition, When used, it is dissolved in a form of dry aerosol that does not cause ',, sterile water, physiological saline or any other pharmaceutically acceptable agent. A w is intended to be directly inhaled. In combination with a water-soluble solid diluent or vehicle (for example, polydextrose, mannitol or lactose). Preferably, the composition provided herein is a pharmaceutical composition or: one unit: type. Pharmaceutical composition And a single-unit dosage form can comprise a prophylactically or therapeutically effective amount or a plurality of prophylactic or therapeutic agents (eg, a compound of formula (I) or other prophylactic or therapeutic agent), and typically comprises one or more pharmaceutically acceptable carriers. Or an excipient. In a particular embodiment and herein, 'stomach gastrointestinal pharmaceutically acceptable' means approved by the regulatory agency of the federal or state government, or as applicable to animals and more specific words. In the US Pharmacopeia or other recognized pharmacopoeia. The term "carrier" refers to a diluent or adjuvant that is administered with a therapeutic agent (eg, __d's adjuvant) (complete and incomplete) , excipients or vehicles. These pharmaceutical carriers may be sterile liquids such as water and oils, including petroleum, animal, vegetable or synthetic oils such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred carrier when administered intravenously. The physiological saline solution and aqueous dextrose and glycerol solutions can also be used as a liquid carrier, especially for injectable solutions. Examples suitable for pharmaceutical carriers. Described in Ew Martin, "Remingt〇n, s 152269.doc • 46- 201121958

In Pharmaceutical Sciences. Typical pharmaceutical compositions and dosage forms comprise - ten ☆ ^ ^ 3 or more excipients. Suitable excipients are well known to those skilled in the art, and non-limiting examples of suitable excipients include powder, glucose, lactose, gelatin, malt, rice, flour, white peony, lycopene, stearin. It is known that sodium sulphate, glyceryl monostearate, talc, sodium carbonate, skim milk powder, glycerin, glycerol, water, ethanol and the like. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form will depend on a variety of factors well known in the art, including, without limitation, the manner in which the dosage form is administered to the individual and the particular activity in the dosage form. ingredient. The composition or single-unit dosage form may also contain minor amounts of wetting or emulsifying agents or pH buffering agents if desired. Lactose-free compositions may comprise excipients well known in the art and listed, for example, in the United States Pharmacopoeia (10) P) SP (XXI) / NF (XVI). In general, lactose-free compositions comprise pharmaceutically compatible and A pharmaceutically acceptable amount of active ingredient, binder/filler, and 1 bone agent. <Listed non-dairy _ type contains active ingredient, microcrystalline cellulose, pregelatinized starch and magnesium stearate. Also provided herein are anhydrous pharmaceutical compositions and dosage forms comprising the active ingredient, as water promotes degradation of some of the compounds. For example, the addition of water (e.g., 5%) is widely accepted in medical technology as a method of simulating long-term storage to determine characteristics of the formulation over time, such as shelf life or stability. See, for example, T. Carstensen, Drug Stability: Principles & Practice, 2nd ed., Marcel Dekker, NY, NY, 1995, p. 379 80. In fact, water and heat accelerate the decomposition of some compounds. Therefore, the effect of water on the formulation is significant because it is often exposed to moisture and/or full gas during storage, handling, storage and storage of the formulation. Anhydrous pharmaceutical compositions and dosage forms can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms comprising lactose and at least one active ingredient comprising a -grade amine or a secondary amine are preferably anhydrous if it is intended to be in substantial contact with moisture and/or moisture during manufacture, packaging and/or storage. . Anhydrous pharmaceutical compositions should be prepared and stored such that they retain anhydrous character. Accordingly, it is preferred to use a material that is known to prevent contact with water, such that it can be included in a suitable kit. Examples of suitable packaging include, but are not limited to, sealed, plastic, unit dose containers. (eg vials), blister packs and strip packs. Further provided herein are pharmaceutical compositions and dosage forms that comprise - or a plurality of compounds that reduce the rate of decomposition of the active ingredient. Such compounds are referred to herein as "stabilizers" and include, but are not limited to, antioxidants (such as ascorbic acid), pH buffers or salt buffers. The pharmaceutical compositions and single unit dosage forms may be in the form of solutions, suspensions, emulsions, lozenges, pills, capsules, powders, sustained release formulations, and the like. Oral formulations may include standard carriers such as pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Such compositions and dosage forms will contain a prophylactic or therapeutically effective amount of a prophylactic or therapeutic agent in the form of a purified form, together with a suitable amount of carrier, in a form suitable for administration to the individual. The formulation should be adapted to the mode of administration. In a preferred embodiment, the 'pharmaceutical composition or single unit dosage form is sterile and in a suitable form for administration to an individual, preferably an individual animal, a better mammal, 152269.doc • 48-201121958, and preferably Human individual. The pharmaceutical compositions provided herein are formulated to be compatible with their intended route of administration. Examples of routes of administration include, but are not limited to, parenteral, such as intravenous, intradermal, subcutaneous, intramuscular, subcutaneous, oral, buccal, sublingual, inhalation, intranasal, transdermal, topical, transmucosal, Intratumoral, intrasynovial and rectal administration. In a particular embodiment, the composition is formulated according to conventional procedures into a pharmaceutical composition suitable for intravenous, subcutaneous, intramuscular, oral, intranasal or topical administration to humans. In one embodiment, the pharmaceutical composition is formulated for subcutaneous administration to humans according to conventional procedures. The composition for intravenous administration is usually a solution in a sterile aqueous buffer. If necessary, the composition may also include a solubilizing agent and a local anesthetic such as lidocaine to reduce pain at the injection site. Examples of dosage forms include, but are not limited to, lozenges; caplets; capsules, such as elastic soft gelatin capsules; cachets; sugar-coated tablets; buccal ingots; dispersions; test agents, ointments, cataplasms/oultices Paste; powders; dressings; creams; gypsum; solutions; tablets; aerosols (such as nasal sprays or inhalants); gels; liquid formulations suitable for oral or transmucosal administration to individuals, including suspension Liquid (eg, aqueous or non-aqueous liquid suspension 'oil-in-water emulsion or water-in-oil liquid emulsion), solution and expectorant; liquid dosage form suitable for parenteral administration to an individual; and reversible to provide a suitable parenteral Sterile solids (e.g., crystalline or amorphous solids) that are administered to a liquid dosage form of the individual. The composition, shape and type of dosage form will generally vary depending on its use. For example, a dosage form for initial treatment of a viral infection can contain one or more active ingredients in an amount greater than the dosage form used to maintain the same infection in the treatment of 152269.doc • 49-201121958. Similarly, a parenteral dosage form can contain one or more active ingredients in an amount that is less than the oral dosage form used to treat the same disease or condition. These and other ways in which particular dosage forms can vary from one another to those skilled in the art will be readily apparent. See, for example, Remington's Pharmaceutical Sciences, 18th Edition, 'Mack Publishing, Easton PA (1990). In general, the ingredients of the compositions provided herein are provided separately or separately in unit dosage form, for example, as a dry lyophilized powder or a water-free concentrate in a closed container (such as an ampoule or sachet indicating the amount of active agent) The form in the middle. When the composition is to be administered by infusion, the composition may be dispensed with a drop containing sterile pharmaceutical grade water or physiological saline. # When the composition is administered by injection, an ampule for sterile water for injection or physiological saline can be provided so that the ingredients can be mixed before administration. A typical dosage form comprises a compound provided herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof, in the range of from about 10,000 mg per day to about 50,000 mg per day in the form of a single dose per week. Give, "jiaojiao in the form of divided doses and food - take it. The particular dosage form of the invention has about ο.1, 0.2,. , 5.0, 10.0, 15.0, 2〇, 〇, 25 500 or 1000 mg of active agent β oral dosage form 50.0 100, 200, 250, suitable for oral administration of the present and forked medical composition can be individual The form of the dosage form presents 'such as (彳曰 卩卩仏, ^ 1 not limited to) the agent (such as a chewable tablet), a caplet, a capsule, and a liquid (such as biting her, feather syrup). These dosage forms contain a predetermined amount of the active ingredient 152269.doc 201121958 and can be prepared by a pharmacy method well known to those skilled in the art. See generally Remington, Pharmaceutical, "I (2), 18th edition,

Mack Publishing, Easton PA (1990) 〇 In certain embodiments, the π dosage form is solid and is prepared with anhydrous ingredients under anhydrous conditions' as described in detail in the above section. However, other embodiments extend beyond the anhydrous solid oral dosage form. Therefore, other forms are also described herein. A typical oral dosage form is prepared according to conventional pharmaceutical compounding techniques by combining the active ingredient with at least one excipient into an intimate admixture. The excipient can take a variety of forms depending on the form of preparation required for administration. For example, excipients suitable for oral liquid or aerosol dosage forms include, but are not limited to, water, diols, oils, alcohols, flavoring agents, preservatives, and coloring agents. Examples of excipients suitable for use in solids: dosage forms such as powders, lozenges, capsules and caplets include, but are not limited to, starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, adhesives Agent and disintegrant. Because the suspects and capsules are easy to administer, they represent the most advantageous oral dosage unit form, in which case solid excipients are employed. If necessary, the bonding agent can be coated by standard aqueous or non-aqueous techniques. These dosage forms can be prepared by any of the methods of ethics. In general, 'pharmaceutical compositions and dosage forms are prepared by intimately mixing the active ingredient with a liquid carrier, a finely divided solid carrier, or both, and, if desired, shaping the product into the desired form. . For example, a tablet can be prepared by compression or molding. The compressed lozenges can be prepared from the active ingredients in a suitable flow in the form of a free-flowing (such as powder or granule) mixture with excipients as appropriate. Molded lozenges can be prepared by mixing a mixture of powdered compounds which are wetted with an inert liquid in a suitable machine by I52269.doc • 51 - 201121958. Examples of excipients that can be used in the oral dosage form include, but are not limited to, binders, fillers, disintegrants, and lubricants. Adhesives suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch or other natural starches and synthetics such as acacia, sodium alginate, alginic acid, and other brown algae. Acid salt, powdered tragacanth, guar gum, cellulose and its derivatives (such as ethyl cellulose, cellulose acetate, calcium methylcellulose, sodium carboxymethyl cellulose), Polyethylene guanidine, sulfhydryl cellulose, pregelatinized starch, propylmethylcellulose (eg, No. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof. Examples of fillers suitable for use in the medical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powders), microcrystalline cellulose, powdered cellulose, glucose binders ( Dextrate), kaolin, mannitol, citric acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. In some embodiments, the binder or filler in the pharmaceutical compositions provided herein is present in an amount of from about 50 to about 99 weight 〇/〇 of the pharmaceutical composition or dosage form.

Suitable forms of microcrystalline cellulose include, but are not limited to, AVICEL PH 101, AVICEL PH 103 AVICEL RC 581, AVICEL PH 105 (available from FMC Corporation, American Viscose Division,

Avicel Sales, Marcus Hook, PA) and mixtures thereof. The specific binder is a mixture of microcrystalline cellulose and dimethicone cellulose sold as AVICEL RC 581. Suitable for anhydrous or low-moisture excipients or additions 152269.doc •52- 201121958 Agents include AVICEL PH 1〇3tm and Starch 1500 LM. In some embodiments, a disintegrant is used in the compositions provided herein to provide (d) when exposed to an aqueous environment (d). Tablets containing too much disintegrant can disintegrate upon storage, while tablets containing too little disintegrant may not disintegrate at the desired rate or under the desired conditions. Because of &, a sufficient amount of disintegrant (neither too much or too little, so as not to adversely alter the release of the active ingredient) should be used to form the solid oral dosage form of the present invention. The amount of disintegrant used varies based on the type of formulation and can be readily discerned by one of ordinary skill. A typical pharmaceutical composition comprises from about 0.5 to about 15% by weight of a disintegrant, specifically from about i to about $% by weight of a disintegrant. Disintegrators which can be used in pharmaceutical compositions include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline fibroin, croscarmellose sodium, crospovidone, and pollackin unloading (p 〇lacrilin p〇tassium), sodium glycolate acetate, potato or tapioca starch, pregelatinized starch, other starches, clay, other alginate, other cellulose, gums, and mixtures thereof. Lubricants useful in pharmaceutical compositions and dosage forms include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerol, sorbitol, mannitol, polyethylene Alcohol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil zinc stearate, ethyl oleate, bay laurel Ethyl acetate, agar and mixtures thereof. Other lubricants include, for example, syloid silica gel (AEROSIL 200, by WR

Grace Co., manufactured by Baltimore, MD), condensed aerosol of synthetic cerium oxide (commercially available from Degussa Co., Plano, TX), CAB O SIL (by Cabot 152269.doc -53- 201121958

The pyrogenic cerium oxide product sold by Co., Boston, ), and mixtures thereof, if used correctly, are typically employed in amounts less than about 1% by weight of the pharmaceutical composition or dosage form. Delayed Release Dosage The active ingredient can be administered by controlled release methods or delivery devices well known to those of ordinary skill in the art. Examples include, but are not limited to, U.S. Patent Nos. 3,845,77; 3,916,899; 3,536,809; 3,598,123; and 4'008,719, 5,674,533, 5,059,595, 5'591, Each of the items is incorporated herein by reference in its entirety by reference in its entirety in its entirety in the the the the the the the the the the the the the the the the the the the Such dosage forms can be used to provide slow or controlled release of one or more active ingredients using, for example, hydroxypropyl methylcellulose, other polymeric matrices, gels, permeable membranes, osmotic systems, multi-layer coatings, microparticles, lipids The body, microspheres, or a combination thereof, provides the desired release profile at different ratios. Suitable controlled release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients provided herein. Accordingly, provided herein is a single unit dosage form suitable for oral administration suitable for controlled release, such as, but not limited to, a key, a capsule, a gelcap, and a caplet. All controlled release drugs have a common goal of improving drug therapy beyond what is achieved by their non-control counterparts. Ideally, the use of an optimally designed controlled release formulation in medical therapy is characterized by the use of a minimal amount of the drug to cure or control the condition in a minimum amount of time. Advantages of controlled release formulations include drug activity expansion, reduced dosing frequency, and individual compliance. 152269.doc • 54· 201121958 The same. Additionally, controlled release formulations can be used to affect the onset of action or other characteristics, such as the blood level of the drug, and thus can affect the appearance of side effects, such as adverse effects. Most controlled release formulations are designed to initially release a certain amount of the drug (active ingredient) such that the desired therapeutic effect is immediately produced, and other amounts of the drug are gradually and continuously released to maintain this degree of therapeutic or prophylactic action for a prolonged period of time. To maintain this constant drug content in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug that is metabolized and excreted from the body. Controlled release of the active ingredient can be stimulated by a variety of conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds. Parenteral dosage forms Parenteral dosage forms are provided herein. Parenteral dosage forms can be administered to the individual by a variety of routes including, but not limited to, subcutaneous, intravenous (including rapid injection), intramuscular, and intraarterial. Because parenteral dosage forms generally circumvent the individual's natural anti-purple effect on the contaminant, it is preferably sterile or sterilizable prior to administration to the individual. Examples of parenteral dosage forms include, but are not limited to, the solution to be injected, the dry product to be dissolved or suspended in a pharmaceutically acceptable injectable vehicle, the suspension to be injected, and the emulsion. Suitable vehicles for providing parenteral dosage forms are well known to those skilled in the art. Examples include, but are not limited to, 11 hydrazine for injection; aqueous vehicles such as, but not limited to, sodium sulphate injection, Ringer's injection, dextrose injection, dextrose, and sodium chloride injection. Liquid, and lactated Ringer's injection; water-miscible vehicles such as, but not limited to, ethanol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as (but not limited to 152269.doc • 55- 201121958 Yu) corn #, cottonseed oil, peanut oil, sesame oil, oleic acid B s, fourteen succinic acid isopropyl S and benzoic acid benzoic acid. Compounds which increase the solubility of the active ingredients disclosed herein may also be incorporated into parenteral dosage forms. Percutaneous, topical, and transmucosal dosage forms Percutaneous, topical, and transdermal formulations are also provided herein. Percutaneous, topical, and transmucosal dosage forms include, but are not limited to, ophthalmic solutions, sprays, aerosols, creams, lotions, ointments, gels, solutions, emulsions, suspensions, or solutions known to those skilled in the art. Other forms. See, for example, Remington, s Pharmaceutical Sciences, ^ Mack Publishing,

Easton PA (1980 ^ 1990); ^ Introduction to Pharmaceutical Dosage Forms, 4th edition, Lea and Febiger, Philadelphia (1985). A dosage form suitable for treating oral mucosal tissue can be formulated as a mouthwash or an oral gel. In addition, transdermal dosage forms include "reservoir type" or "matrix type" patches which can be applied to the skin and applied for a specific period of time to allow penetration of the desired amount of active ingredient. Suitable excipients (e.g., carriers and diluents) and other materials which may be used in transdermal, topical and transmucosal dosage forms are well known to those skilled in the art, and will depend on the particular tissue to which a given pharmaceutical composition or dosage form will be applied. And set. It should be understood that 'typical excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane 1,3 diol, isopropyl myristate, palmitic acid isopropyl, minerals Oils and mixtures thereof to form non-toxic and pharmaceutically acceptable lotions, elixirs, creams, lotions, gels or ointments. A moisturizer (Moisturizer) or a humectant may also be added to the pharmaceutical composition and dosage form as necessary. 152269.doc -56- 201121958 Examples of such other ingredients are well known in the art. See for example

Remington’s Pharmaceutical Sciences, 16th and 18th editions, Mack Publishing, Easton PA (1980 and 1990). Depending on the particular tissue being treated, other components may be used prior to, concurrently with, or after treatment with the active ingredients, including but not limited to the compounds provided herein. For example, penetration enhancers can be used to help deliver the active ingredient to the tissue. Suitable penetration enhancers include, but are not limited to: acetone; various alcohols such as ethanol, oleyl alcohol, and tetrahydrofuranol; alkyl alum, such as disulfoxide, dimethylacetamide; dimethylformamidine; Amine; polyethylene glycol; pyrrolidinium 'such as polyethylene η piroxime; K〇1lid〇n grade (P〇Vld〇ne), polyvinylpyrrolidone (Polyvidone) ;); urea; and various water-soluble or water-insoluble sugar esters, such as Tween 8 (polysorbate 8) and Span 60 (sorbitan monostearate). The pH of the pharmaceutical composition or dosage form, or tissue coated with the pharmaceutical composition or agent can also be adjusted to improve the delivery of one or more active ingredients. Similarly, the polarity of the solvent carrier, its ionic strength or tension can be adjusted to improve delivery. A compound such as a stearate may also be added to the pharmaceutical composition or agent, ', advantageously to modify the hydrophilicity or lipophilicity of one or more of the active ingredients, in order to improve delivery. In this regard, the stearate can act as a lipid vehicle for the formulation as a ritual or surfactant, and as a delivery enhancer or a different salt, hydrate or solvate of the active ingredient of the penetration and redness agent. To further adjust the properties of the resulting composition. Dosage and unit dosage form in humans ~ therapeutics 'doctors will be based on preventive or curative treatment and root 152269.doc •57· 201121958 according to the specific age, weight, infection stage and other factors of the individual The most appropriate dosimetry is considered. Generally, for an adult, the dosage is from about 1 mg to about 1000 mg per ounce, or from about 5 to about 250 mg per ounce for adults, or from about 丨〇 mg to 5 mg per ounce. In certain embodiments, the agent is from about 5 mg to about 100 mg per day, and more preferably from mg to 2 mg per day. A dosage rate of about 5 〇 mg to about 5 每日 per day is also preferred. In other aspects, the present invention provides a high therapeutic index for hepatitis C virus by administering an effective amount to an individual in need thereof. A method of treating or preventing a hepatitis C virus infection in an individual by a compound of the invention or a pharmaceutically acceptable salt thereof. The therapeutic index can be measured according to any method known to those skilled in the art, such as the methods described in the Examples below. In certain embodiments, the therapeutic index is the ratio of the concentration at which the compound is toxic to the concentration effective against the hepatitis C virus. Toxicity can be measured by any technique known to those skilled in the art, including cytotoxicity (eg, ICso or ICM and lethal dose (eg, LD5〇 or LD9〇). Similarly, effective concentrations can be obtained by those skilled in the art. Any technical measurement is known, including effective concentrations (eg, Ec^ or EC%) and effective doses (eg, Ehp'ED9.). Preferably, similar measurements are compared in ratios (eg, IC5〇/EC5q, IC9G/EC9Q). , LD5Q/ED5〇 or LD9Q/ED90). In certain embodiments, the therapeutic index can be as high as 2.0, 5.0, 10.0, 15, 0, 20.0, 25.0, 50.0, 75.0, 100.0, 125.0, 150.0 or more. Or the effective amount of the composition to prevent, treat, manage or ameliorate the condition or one or more of its symptoms will vary depending on the nature and severity of the disease or condition and the route of administration of the ingredient 152269.doc-58-201121958. The dosage will also depend on the particular factor of each individual 'depending on the particular therapy (eg, therapeutic or prophylactic) administered, the severity of the condition, disease or condition, the route of administration, and the age, body, weight, and The clinical dose varies. The effective dose can be extrapolated from the dose-response curve derived from an in vitro or animal model test system. Exemplary dosages of the composition include milligrams or micrograms of active compound per kilogram of individual or sample weight (eg, about 10) Micrograms/kg to about 50 mg/kg, from about 100 micrograms/kg to about 25 mg/kg, or from about 100 micrograms/kg to about 10 mg/kg. For the compositions provided herein, 'by weight of active compound' The dosage administered to the individual is usually from 0.140 mg to 3 mg per kg of body weight. In one embodiment, the dosage administered to the individual is between 0.20 ng and 2. 〇〇mg per kg of body weight, or at 〇3 The bark is between 1.50 mg. In one embodiment, the recommended daily dose for the treatment or prevention of HCV infection in the compositions provided herein is in the range of from about 0.1 mg to about 1000 mg per day, once daily. The sub-dose is administered in the form of a divided dose throughout the day. In the case of a single dose, the sputum dose is administered twice daily in aliquots. Du francs - 5' dose range Should be for each About i 〇mg to about 200 mg, P wins one + +, ^ more special 5, between about 1 〇 mg and about 15 〇 mg per day, or even more specifically about 25 pm per week Between _ _ oh. In some cases, it may be necessary to use the active ingredient / knife dose outside the scope disclosed in this article, which will be obvious to 10,000, slave technicians. In addition, 'tolerate the clinician 岑, Hey, hemp s. Therapist will combine individual reactions to understand how and when to interrupt, regulate or terminate therapy. 152269.doc •59· 201121958 Different therapeutically effective amounts can be applied to different diseases and conditions, as will be readily known to the general practitioner. Similarly, the above dosages and dosing frequency schedules will also cover sufficient to prevent, manage, treat or ameliorate such conditions, but not sufficient to cause adverse side effects associated with the compositions provided herein, or sufficient to reduce such adverse effects. the amount. In addition, not all doses need to be the same when administered to a plurality of dosages of the compositions provided herein. For example, the agent administered to an individual can be administered to improve the prophylactic or therapeutic effect of the composition, or the dosage administered to the individual can be reduced to reduce one or more side effects experienced by the particular individual. In one particular embodiment, the dosage of a composition provided herein to be administered to prevent or treat a condition of the individual or one or more symptoms thereof, by weight of the active compound, is per kg body weight. i mg, 1 Mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 1 mg or 15 mg or more. In another embodiment, the dosage of the composition administered to prevent, treat, manage, or ameliorate the condition of the individual or one or more symptoms thereof is the following unit dose: 0.1 mg to 200 mg, 0.1 mg to 100 mg, 0.1 mg to 50 mg, 0.1 mg to 25 mg, 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.1 mg to 10 mg, 0.1 mg to 7.5 mg, 0.1 mg to 5 mg, 0.1 to 2.5 mg, 0.25 mg to 20 mg, 0.25 to 15 mg, 0.25 to 12 mg, 0.25 to 10 mg, 0.25 mg to 7.5 mg, 0.25 mg to 5 mg, 0.5 mg to 2.5 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg Up to 12 mg, 1 mg to 10 mg, 1 mg to 7.5 mg, 1 mg to 5 mg, or 1 mg to 2.5 mg. In certain embodiments, the treatment or prevention may be initiated by one or more starting doses of a compound or composition provided herein, followed by one or more maintenance doses. In such embodiments, the starting dose can be, for example, about 60 mg to 152269.doc • 60 to 201121958, about 400 mg per ounce, or about loo mg to about 2 mg per ounce, for one to five weeks. The starting dose can be followed by one or more maintenance doses. Each maintenance dose may independently be from about 10 mg to about 200 mg per day, more specifically between about 25 mg and about 150 mg per sputum, or even more specifically at about mg and about 80 mg per guanidine. between. The maintenance dose is preferably administered per ounce and can be administered in a single dose or in divided doses. In certain embodiments, the dosage can be administered to achieve a steady state concentration of the active ingredient in the blood or serum of the individual. The steady state concentration can be determined by measurements made according to techniques available to those skilled in the art, or can be based on the physical characteristics of the individual, such as height, weight, and age. In certain embodiments, a sufficient amount of the compound or composition is administered to achieve from about 3 ng/mL to about 4000 ng/mL, from about 400 ng/mL to about 16 ng/mL in the blood or serum of the individual. ,or

A steady state concentration of from about 600 ng/mL to about 1200 ng/mL. Can be administered in the starter to achieve about 1200 ng/mL to about 8000 ng/mL' or about 2000 ng/mL

Steady blood or serum concentrations up to 4000 ng/mL for one to five days. And / or, to achieve the individual's blood or serum about ng / mL to about 4000 ng / mL, about 4 ng / mL to about l6 〇〇, or about 6 〇〇 ng / mL to about Steady state concentration of 12 ng/mL. In some embodiments, the same composition can be repeatedly administered and such investments can be separated by j/1, 2, 3, '5 days, 1 () day, 15 days, 30 days, 曰 2 Month, 75, 3 or 6 months. In other embodiments, the same-preventive or therapeutic agent may be administered repeatedly and the administration may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 days. Month, 75, 3 or 6 months. 152269.doc -61 - 201121958 In certain aspects, provided herein is a unit dosage comprising a compound of formula (1), or a pharmaceutically acceptable salt thereof, in a form suitable for administration. These forms are described in detail above. In certain embodiments, the unit dose contains from i to 1000 mg, from 5 to 250 mg, or from 10 to 5 mg of active ingredient. In a particular embodiment the 'unit dose contains about! , 5, 10, 25, 5 〇, 1 〇 (), 125, 250, 500 or 1000 mgs of sexual ingredients. These unit dosages can be prepared according to techniques familiar to those skilled in the art. Kits This article also provides kits for use in methods for treating or preventing HCV infection. Such kits can include the compounds or compositions provided herein, as well as instructions for providing health care providers with information regarding the use of the treatment or prevention of Hcv infection. 35 The book may be provided in printed form or in the form of electronic media (such as a floppy disk, CD or DVD) or in the form of a website address at which such instructions are available. A unit dosage of a compound or composition provided herein can include, when administered to an individual, the therapeutic or prophylactic plasma levels of the compound or composition in an individual to be sustained for at least a daily dose. In some embodiments, the compounds or compositions provided herein can be included in the form of a sterile aqueous pharmaceutical composition or a dry powder (e.g., lyophilized) composition. In some embodiments the 'compound is according to formula (1). In some embodiments, a suitable package is provided. As used herein, "packaging" refers to a solid matrix or material that is conventionally used in a system and capable of holding a compound or composition provided herein to a fixed limit within a fixed limit, such as glass and plastic (eg, Polyethylene, polypropylene and polycarbonate bottles, vials, paper, plastic 'and plastic _ knot laminated bags and 152269.doc -62· 201121958 analogs. If electron beam sterilization techniques are employed, the package should have a sufficiently low density to sterilize the contents. The kits provided herein may also comprise, in addition to a compound of formula (I) or a composition thereof, other compounds or compositions for use with a compound of formula (1) or a combination thereof, as described in the above methods. Combination Therapy The compounds provided herein can also be combined with, or used in combination with, other therapeutic agents suitable for the treatment and/or prevention of HCv infection. As used herein, the term "combination" includes the use of more than one therapy (e.g., one or more prophylactic and/or therapeutic agents). However, the use of the term "combination" does not limit the order in which an individual's therapy (e.g., prophylactic and/or therapeutic agent) is administered to a disease or condition. The first therapy (eg, a prophylactic or therapeutic agent, such as a compound provided herein) can be prior to administration of a second therapy (eg, a prophylactic or therapeutic agent) (eg, 5 minutes, 15 minutes, 3 minutes, minutes, minutes, i Hour, 2, 4, 6, 12, 24, 48, 72, 96, 1, 2, 3, 4, 5 , at the same time or after (after 5 minutes, 15 minutes, 3 minutes, 45 minutes, 1 hour, 2 hours, 4 ^ Μ, hour, 丨 2 hours, 24 hours, 48 hours, 72 hours, 96 hours H, 3 The individual is administered weekly, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks. This article also covers three-in-one therapy. 0. 匕 本文 This article provides 缸, which has been or is currently being used to treat, prevent, or manage..., - therapies (such as prophylactic or therapeutic agents), '3 conditions: ° The addition of plants to therapy; 152269.doc •63· 201121958 should be more effective. The synergistic effect of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) allows for the frequency of such treatments to be administered to a subject having a lower dose of one or more therapies and/or a smaller one. The ability to administer the therapy with a lower dose of therapy (e.g., a prophylactic or therapeutic agent) and/or at a lesser frequency reduces the toxicity associated with administering the therapy to the individual, while the therapy is less effective than preventing or treating the disorder The effect in the middle. In addition, synergistic effects may result in improved efficacy of the agent in preventing or treating a condition. Ultimately, the synergistic effect of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) can avoid or reduce the adverse or undesirable side effects associated with the use of either of the individual therapies. The compounds provided herein can be administered in combination with another therapeutic agent such as anti-11 (: another agent). In combination therapy, an effective dose of two or more agents is administered together, in alternating or sequential steps. In therapy, an effective dose of each agent is administered continuously or sequentially. The dose administered will depend on the absorption, inactivation, and excretion rates of the drug and other factors known to those skilled in the art. It should be noted that the dose will also follow It is to be understood that the severity of the condition to be ameliorated should be further understood. For any particular individual, the specific course of administration should be adjusted over time according to the individual's needs and the professional judgment of the person administering or supervising the administration of the composition. % recognizes drug resistance = allogeneic that may occur after long-term antiviral therapy. Drug resistance is most commonly caused by genes encoding enzymes used in viral replication, by inducing mutations that are different from those caused by major drugs. Perhaps the efficacy of the third antiviral compound in combination or alternation of the compound's drug against a viral infection may be prolonged, enhanced or restored. The kinetics, biodistribution, or other parameters can be altered by this combination or alternation therapy. In general, combination therapy is generally superior to alternation therapy because it simultaneously induces multiple stresses to the virus. HCV protease inhibitors include, but are not limited to, Medivir HCV protease inhibitors (Medivir/Tobotec); ITMN-191 (InterMune), SCH 503034 (Schering), VX950 (Vertex); based on the substrate as disclosed in the following literature NS3 protease inhibitors: WO 98/22496; Attwood et al, Antiviral Chemistry and Chemotherapy 1999, 10, 259-273; DE 19914474; WO 98/17679; WO 99/07734; non-based NS3 protease inhibitors, such as 2,4,6-Tris-methyl-3-stone succinyl-crackamine derivatives (Sudo et al., oc/iew. Biophys. Res. Commun. 1997, 238, 643-647) 'RD3-4082 ' RD3 -4078, SCH 68631 and Philippine (Chu et al., Tetrahedron 1996, 37, 7229-7232); SCH 35 1633 (Chu et al., Bioorganic and Medicinal Chemistry Letters 1999, 9, 1949-1952); Eglin c, an effective Polymerase inhibitors (Qasim et al, Biochemistry 1997, 36, 1598-1607) ° Other suitable protease inhibitors for the treatment of HCV include, for example, those disclosed in U.S. Patent No. 6,004,933, which discloses a class of HCV endopeptidase 2 cysteine protease inhibitors. Other Hepatitis C virus NS3 protease inhibitors include those disclosed in the following literature: for example, Llin^s-Brunet et al., 5/Sigh from 6/.0/^. B6". 1998, 1713-1718 ; Steinkiihler et al., 1998, 37, 8899-8905; U.S. Patent No. 5,538,865; 5,990,276; 6,143,715; 6,265,380; 6,323,180; 6,329,379 152269.doc-65-201121958; No. 6,410, 531; No. 6,534, 523; No. 6,642,204; No. 6,653, 295; No. 6, 727, 366; No. 6, 838, 475; No. 6, 846, 802; No. 6, 867, 185; No. 6, 869, 964; No. 6, 872, 805; No. 6, 878, 722; Nos. 6,908,901; 6,911,428; 6,995,174; 7,012,066; 7,041,698; 7,091,184; 7,169,760; 7,176,208; 7,208,600 U.S. Patent Application Publication No. 2002/0016294, No. 2002/0016442, No. 2002/0037998, No. 2002/0032175, No. 2004/0229777, No. 2005/0090450, No. 2005/0153877, No. 2005/ 176648; No. 2006/0046956; 2007/0021330; 2007/0021351; 2007/0049536; 2007/0054842; 2007/0060510; 2007/0060565; 2007/0072809 ; 2007/0078081; 2007/0078122; 2〇07/0093414; 2007/0093430; 2007/0099825; 2007/0099929; 2007/0105781; WO 98/17679; WO 98/22496; WO 99/07734; WO 00/059929; WO 00/09543; WO 02/060926; WO 02/08187; WO 02/008251; WO 02/008256; WO 02/08198; WO 02/48116; WO 02/48157; WO 02/48172; WO 03/053349; WO 03/064416; WO 03/064456; WO 03/099274; WO 03/099316; WO 2004/032827; WO 2004/043339; WO 2005/037214; WO 2005/037860; WO 2006/000085; WO 2006/119061; WO 2006/122188; WO 2007/001406; WO 200 7/014925; WO 2007/014926; and WO 2007/056120. Other protease inhibitors include thiazole derivatives, such as RD-1 - 152269.doc -66 - 201121958 6250, RD4 6205 and RD4 6193, which display the NS3/4A fusion protein and NS5A/5B substrate in a reverse phase HPLC assay. Related inhibition (Sudo et al., 1996, 9-18); Sit and aniline aniline, which is identified in the following literature: Kakiuchi et al., corpse £55 Lett. 1998, 42 VIII 217-220; Takeshita et al., less "ca/ Biochemistry 1991, 247, 2A2-246 . Suitable non-nucleoside HCV polymerase inhibitors include, but are not limited to, A-848837 (Abbott), gliotoxin (Ferrari et al., 々 ""Shen / 〇 / Wro/og less 1999, 73, 1649-1654), and the natural product cerulenin (Lohmann et al, KiVo/ogjv 1998, 249, 108-118). Suitable nucleoside HCV polymerase inhibitors include, but are not limited to, 1171280· Hoffmann-La Roche Ltd., Basel, Switzerland) ' PSI-7851

(Pharmasset, Inc., Princeton, NJ), PSI-352879 (Pharmasset, Inc., Princeton, NJ), PSI-352938 (Pharmasset, Inc., Princeton, NJ), IDX184 (Idenix Pharmaceuticals, Inc., Cambridge, ΜΑ ' INX-189 (Inhibitex, Inc., Alpharetta, GA) and the compounds described in U.S. Patent Nos. 6,660,721; 6,777,395; 6,784,166; 6,846,810; 6,914,054; 6,927,291 No. 7,094,770; No. 7,105,499; No. 7,125,855; and No. 7,202,224; U.S. Patent Publication No. 2004/0121980; No. 2005/0009737; No. 2005/0038240; No. 2006/0040890; No. 2008/0286230; WO 99/43691; WO 01/32153; WO 01/60315; WO 01/79246; WO 01/90121 'WO 01/92282 > WO 152269.doc -67- 201121958

02/18404; WO 02/32920, WO 02/48165, WO 02/057425; WO 02/057287; WO 2004/002422, WO 04/002999 and WO 04/003000. Suitable cyclophilin modulators include, but are not limited to, cyclosporin (e.g., cyclosporin A), anti-cyclin antibodies (see, e.g., Yang, F. et al. 'P7ro/og_y, 2008, 82(11): 5269-5278), sanglifehrin A, NIM811 (Novartis AG, Basel, Switzerland); DEBIO-025 (Debiopharm SA, Lausanne, Switzerland), and compounds described in the following documents: U.S. Patent No. 7,439,227 U.S. Patent Publication No. 2007/0275884; No. 2008/0045454 and No. 2009/0221598; WO 05/0021028; WO 06/038088; WO 06/071618; WO 06/23394 and WO 08/043797. Other hybrid compounds that can be used as the second agent include, for example, 1 -amino-homocyclohexane (U.S. Patent No. 6,034,134), alkyl lipids (U.S. Patent No. 5,922,757), vitamin E and other antioxidants (US Patent) No. 5,922,757), squalene, tricyclic guanamine, cholic acid (U.S. Patent No. 5,846,964), N-(phosphonium ethoxide)-L-aspartic acid (U.S. Patent No. 5,830,905), benzene Formamide (U.S. Patent No. 5,633,388), polyadenylation derivatives (U.S. Patent No. 5,496,546), 2',3'-dideoxygen (US Patent No. 5,026,687), benzimidazole (US Patent) No. 5, 891, 874), plant extracts (U.S. Patent No. 5,725,859; 5,837,257; and 6,056,961) and piperidine (U.S. Patent No. 5,830,905)

In certain embodiments, one or more of the compounds provided herein are administered in combination or alternation with an anti-C 152269.doc • 68 - 201121958 hepatitis virus interferon, including but not limited to natural interferon, INTRON ® A (interferon a-2b) and PEGASYS® (Peginterferon a-2a); ROFERON® A (recombinant interferon a-2a), INFERGEN® (interferon alfacon-1), PEG - INTRON® (pegylated interferon a-2b), interferon beta-la, omega interferon, interferon gamma, interferon tau, interferon delta or interferon gamma-lb. In one embodiment, the anti-hepatitis C virus interferon is INFERGEN®, IL-29 (PEG-interferon λ), R7025 (Maxy-a), BELEROFON®, oral interferon a, BLX-883 (LOCTERON® ), omega interferon, MULTIFERON®, medusa interferon, ALBUFERON® or REBIF®. EXAMPLES The following examples illustrate the synthesis of representative compounds of formula (I) used in the methods provided herein. The following examples further illustrate the synthesis of intermediates used in the preparation of compounds of formula (I). These examples are not intended to be limiting, nor are they intended to limit the scope of the invention. It will be apparent that the invention may be practiced otherwise than specifically described herein. Numerous modifications and variations of the present invention are possible in light of the teachings herein, and are therefore within the scope of the invention. Example 1: Preparation of N-(5-t-butyl-2-methoxyphenyl)-2_{4_[2-(hept-4-yl)ethoxy]cain-1-yl}-2 - Indole

152269.doc -69· 201121958 Method A: Intermediate 2: 4-[2Naphthalen-1-yloxy)ethyl]morpholine.

〇Materials·Material quantity (kg) Molecular weight Molybdenum benzene 120 L 92.14 1_Naphthol 23.7 kg 144.17 1.02 equivalents N-gas ethylmorpholine hydrochloride 3〇kg 186.08 1 equivalent Essence clock 0.6 kg 166.0 0.02 equivalent sulfuric acid Tetrabutylammonium hydride 2.7 kg 339.54 0.05 equivalent 50% sodium hydroxide 64.5 kg 40.0 About 10 equivalents of ethyl acetate 45 L 88.11 Gengyuan 45 L 100.2 Diqi methane 69 L 84.93 Add 65 L of demineralized water to feed 64.5 kg 50 % argon oxide in a container. In a separate container fed with 30 kg of N-chloroethylmorpholine hydrochloride, 23.7 kg of 1-naphthol, 2.7 kg of tetrabutylammonium hydrogen sulfate, 120 L of toluene and 0.66 kg of potassium iodide were added. The sodium hydroxide solution was added to a vessel fed with a mixture of N-gas ethylmorpholine hydrochloride over 20 minutes maintaining the temperature at 20-40 °C. The mixture was heated to 90 ° C for 3 hours. The mixture is then cooled to 40-45 ° C and maintained until the reaction is complete. If the reaction is completed less than 95%, the reaction mixture is heated to 90 ° C for 1 hour and resampled as before. 152269.doc -70- 201121958 Add 102 L of demineralized water to the mixture so that the temperature does not rise above 5 〇^. In some cases, there are three phases, a lower orange aqueous phase, a middle black phase, and an upper light green organic phase. The orange aqueous phase was separated from the mesophase at 4 (TC). The organic phase was washed with 60 L of demineralized water (15 min, 15-25). The toluene was distilled from the organic phase at <20 mbar. The resulting organic phase was cooled to 40 ° C under a nitrogen atmosphere and 15 L of ethyl acetate and 15 L of heptane were added. The temperature was raised to 60. (: and a vacuum was slowly added to evaporate the solvent. This process was repeated once and sampled. Determine the content of benzene. If the benzene content is more than 0.3%, distill the mixture as before. Increase the temperature to 60 °C again and slowly add vacuum to steam the solvent, cool to 25 °C and add 69 L two gas And the mixture was stirred for 15-20 minutes. Yield: 35.5 kg, 85.6% (96.0% pure) Intermediate 4: {4-[2-(morpholin-4-yl)ethoxy]naphthalene-l -keto(hexyl)hexanoic acid

Materials and Materials Intermediate 2 Dioxane Solution Methyl Ethylene Dioxane Chlorinated Chloride

Clarcel DIC (filter aid) Amount (kg) Molecular weight 31 kg (32.3x96.03% pure) 257.3 39.8 kg 122.51 434 L 84.9 43.4 kg 134.34 108.5 kg 152269.doc -71· 201121958

Hydrochloric acid 279 L 36.5 Mercapto-tert-butyl ether 252 L 88.2 Acetone 168 L 58.1 Ethanol 252 L Add 39.8 to 43.4 kg of aluminum chloride and 434 L of dioxane at 10-23 ° C with stirring. Kg B dioxin. The mixture was then rinsed with 62 L of dioxane and 108.5! <^(: 41^1〇1 (: filter aid) was added. 3 1 kg of intermediate 2 was added to the dioxane over 30 minutes. 2 (The temperature of TC is maintained for a minimum of 16 hours. Slowly add 77.5 kg of demineralized water while controlling the temperature at 2 〇 30 ° C. The resulting mixture is stirred vigorously at 20-25 ° C for 1-2 hours. Solid and washed with dioxane (186 L). Any aqueous phase was separated from the organic phase. Dichloromethane was then distilled at 55_6 ° C under atmospheric pressure until about 500 L remained. Add 310 L of demineralized water Continue to steam at 75-80 °C until the second gas chamber is eliminated. Cool the mixture to 65_70 ° C and add 325 kg of hydrochloric acid while maintaining the temperature at 7 f C for 16 hours. About 30 starts after the clock Crystallization. The mixture is then cooled to ye to 2 ° C for at least 3 hours. The resulting cake is washed with an acid wash prepared by mixing 77. 5 L of hydrochloric acid with 77 5 ^ demineralized water, which cake is then Washed three times with 84 L (each) ethanol, twice with 84 L (each) acetone, and 84 L (mother-human) methyl tert-butyl ether Dilute three times. Dry the cake at no more than (9) c. Yield: 24 6 kg, 55 〇% (96% pure) Ν-(5·t-butyl-2-methoxyphenyl) _2 {4_[2_(morpholine-4-yl)ethoxy]Cai-1-yl}-2-benylamine. 152269.doc -72- 201121958

H3c, 0

H3c-t^ch3 ch3 h30 p h3c^-^ h3c Cl

Et3N, CH2CI2

Material: Amount (g) Molecular weight Molmers equivalent 2.2 365 0.006027 1.1 1.31 120 0.010917 2 1.66 101 0.016436 3 0.98 179 0.005475 1 Material intermediate 4 Trimethylacetamethylene triethylamine 5-(t-butyl)_2 _Methoxyaniline 2.2 g Intermediate 4 was treated with 40 ml of di-methane and 66.66 g of triethylamine. Mixture H is stirred to provide a solution. The solution was then treated by slowly adding 〇66 g of trimethylacetamidine, followed by stirring the mixture for a few hours. The mixture was evaporated in vacuo and the residue was treated with 30 mL of benzene and then evaporated in vacuo to remove excess trimethyl ethane. The residue was dissolved in 30 ml of dichloromethane, and 0.98 g of 5-(t-butyl)-2-methoxyaniline dissolved in 1 〇 1 丨 methane was added. The reaction solution was stirred at room temperature for 1 hour. TLC using 丨0〇/sterol/methylene chloride on cerium oxide showed conversion to product. The reaction mixture was then washed with a volume of 1% K2C03 and the layers were separated. The organic layer was washed again with 10% K 2 C 3 and the layers were separated. The organic layer was then evaporated in vacuo and the residue was taken &lt The obtained solid was collected by filtration, washed with 5 ml of methanol, 5 ml of butyl butyl ether, and air-dried to give N-(5-t-butyl-2-methoxyphenyl)-2- 152269.doc. · 201121958 {4-[2-(morpholine-4-yl)ethoxy]naphthalene_丨_yl b 2 ketodecylamine. Example 2·Preparation of Ν-(5_Tert-butyl-2-methoxyphenyl)_2_{4_[2 (morphin-4-yl)ethoxy]naphthalene_;!_基卜2-keto Indoleamine hydrochloride.

CH3

Ch3

H3C

HCI 12 Μ 二兔炫, CH3CN will be Ν-(5·t-butyl-2-methoxyphenyl)_2_{4_[2·(morpholin-4-yl)ethoxy]naphthalene-1-yl 2 ketodecylamine (1 〇g, i equivalent) was dissolved in a mixture of π% HCl (1. 〇ml, 5 eq.) and dioxane (1 〇ml) and the solution was stirred for 1-2 hours. The solution was evaporated until it was almost dried, and i acetonitrile was added to the residue. After 18 hours at 0 tT, a precipitate was provided. Filtration and washing of the solid with acetonitrile (5 ml) and methyl t-butyl ether (5 ml×2) gave the final product N-(5-t-butyl-2-methoxyphenyl)_2_{4_[2_( Morpholine-4-yl)ethoxy]naphthalen-1-yl}-2-ketopoxime hydrochloride. Method B: Intermediate 2 was prepared as shown in Method A. Intermediate 4: {4-[2-(morpholin-4-yl)ethoxy]naphthalene_;1_yl}(keto)acetic acid.

Formula a 357 40032 Formula = 329.3714 152269.doc 74 201121958 Place a 7 cm 3 gram magnetic stir bar in a 1 L flask, add 32 g of diatomaceous earth 545, dihydromethane, and fill to 700 ml mark. Stirring was started, and 14.5 g of vaporized aluminum and H. 8 ml of ethyl ketone ethyl acetate were sequentially added. The mixture was stirred for 10 minutes, and then a solution of 10.55 g of Intermediate 2 in 60 ml of di-methane was added dropwise over 75 minutes. The next day, the stirring was stopped due to the gelatinous precipitate. After 40 hours, 丨5〇 cm3 of crushed ice was added, and the mixture was stirred to slowly dissolve the dark solid. After the block of the gelatinous substance was dissolved, 2 〇 〇 gasification sodium and 20 ml of hydrochloric acid were sequentially added. After a further 20 minutes of mixing, the mixture was filtered and the filter cake was washed sequentially with 丨〇〇 mi 1 μ hydrochloric acid and 100 ml of dichloromethane. The layers were separated and the digas methane layer was washed with 2 〇〇 ml 10 ° / 〇 potassium carbonate. The potassium carbonate wash solution was extracted with an additional 2 〇〇 mi of two gas methane. The methylene chloride layers were combined and evaporated in vacuo to give &lt The crude dark oil was dissolved in 2M methanol, 10 mL &lt The resulting suspension was treated with 4 Torr of water to provide a turbid solution which was treated with Shiyoshi. The mixture was evaporated in vacuo to provide a dry solid. The solid was dissolved in 4 mL of water, treated with carbon and filtered. The filtrate was neutralized with sulfuric acid to pH 6, and the obtained solid was collected by filtration, washed with water and dried to give 10.28 g of Intermediate 4 as an amino acid. C% H% N% H20°/〇 Experimental value: 62.21 6.32 3.96 5.28 Calculated value: 62.24 6.09 4.03 5.19 Calculated value of C18H19N05xH20 N-(5-t-butyl-2-methoxyphenyl)-2-{ 4_[2-(Methyl-4-yl)ethoxy]phthalen-1-yl}-2-ketopoxime. 152269.doc -75- 201121958 Ο

H3C-i-CH3 An intermediate 4 (7.80 g, 0.022 mol) in a rB flask was treated with 50 ml of dioxane in 25 ml of a magnetic stir bar. Slowly add 5 ml of sulfoxide (0.068 mol). The mixture thickened as the initial 〇 5 ml was added, and another portion of dichloromethane (50 ml) was added to allow stirring. After the addition of sulphide gas, 0.5 ml of dimethyl decylamine was added. After stirring overnight at room temperature, the mixture was placed under a vacuum in the room (about 60 mm Hg) and evaporated until no other condensate was collected in the -20 C trap, and a dry solid was obtained in the reaction flask. A solution of 4.03 g of 5-t-butyl-o-anisidine in 6 ml of di-methane was prepared. The reaction mixture was treated with 50 ml of methane to resuspend the solid. A solution of 5-tert-butyl-o-anisamine was slowly added, followed by 4 ml of 4-methylmorpholine in 丨〇 mi gas. The mixture was then stirred at room temperature for 3 hours. The mixture was transferred to a 500 ml flask to provide a total of 250 such as a gas-fired and 200 ml of a 5% aqueous solution of carbonic acid. After thorough mixing, the layers were separated and the dark yellow organic layer was diluted with 100 ml of decyl alcohol and concentrated. When the volume reaches 250 ml, add 1 〇〇 ml of methanol. Continue to heat concentrate and add 60 ml of methanol when the volume is reduced to 300 ml. Continue to heat concentrate and separate the solids when the vapor temperature of the outlet of the museum reaches 5 7 °C. The heating was terminated and the mixture was allowed to cool with stirring. After stirring over the weekend, the flask containing the solid suspension of 152269.doc •76-201121958 was cooled in an ice water bath and stirred for 4 minutes. The solid was then collected by filtration and dried in air to give 7.23 g of product. Η% N% H20°/〇,, value: 70.71 5.72 0.44 Calculated value: 70.74 5.69 0.37 C29H35C1N2〇5x〇.2 Calculated value of H2〇N-(5-t-butyl-2-methylindolyl) · 2_{4_[2_(morpholine-4-yl)ethoxy] cain-1-yl}-2-keto-amine guanidine hydrochloride.

H3c. HCI 12 Μ 4-mercapto-2-pentaline 18·4 g Ν-(5-t-butyl-2-n-oxyphenyl)_2·{4_[2·(morpholine_4_yl) Ethyl)naphthalen-1-yl}-2-ketopoxime was placed in a 1 L flask with a 4 cm magnetic stir bar. 37 〇 4_methyl 2·pentanone ' 2 such as water was added in order. The mixture was stirred and warmed until a clear yellow solution formed at a temperature of 84 °C. 4 丄 ml of hydrochloric acid was added dropwise over 2 minutes with stirring. After the addition is completed, a thick solid precipitates. The mixture was stirred and allowed to cool. After 4 hours at room temperature, the solid was collected by filtration, washed with 2 χ 2 〇 mi 4 mercapto-2-pentanone, and air dried to provide 18,96 g of N-(5-t-butyl-2- methoxy Phenyl))_2_{4_[2_(?-_4_yl)ethoxy]Cai Xiaoji}_2•嗣-ylamine hydrochloride. N% C1% 5.15 6.42 5.14 6.50 C% Η% Experimental value: 63.95 6.94 Calculated value: 63.90 6 84 Calculated value of C29H34N205xHC1 152269.doc •77· 201121958 Method c: Intermediate 6: Acetic acid 5,2-(naphthalene-1 -Proxyoxy)ethyl ester.

OH

Material: Molecular weight DEN 1-naphthol 144.19 2-bromoethyl acetate 167 1.514 anhydrous potassium carbonate 138 Iodine tetrabutyl 369.38 Molar equivalent weight / Zhao product 0.144461 0.965 20.83 〇0.149701 1 25 g 0.288922 2 39.871 g 0.003357 0.022425 1.24 g In a 200 ml flask, 2·bromoethyl acetate, 20.8 g of 1-naphthene, and 37.8 g of potassium carbonate were placed in this order. 10 〇 mi anhydrous acetone, 丨 24 g moth tetrabutylammonium were added in sequence. The mixture was warmed to 5 (TC. After 48 hours, the mixture was filtered to remove solids. The solid was washed with acetone until the filtrate was almost colorless. The combined filtrate was evaporated in vacuo. Stirring, followed by sedimentation. Evaporation of hexanes in vacuo afforded 28·32 g of a yellow oil of ethyl 2-(naphthalenyl-1-yloxy)ethyl ester. ^11>]1 (: displayed at 254 nM A new peak at 5.35 minutes (73 ° /.), and 2.8% 1-naphthol. Intermediate 7: acetic acid 5,2 · (naphthalen-1 - yloxy) ethyl ester.

14 g of 2-(naphthyl-buyloxy)ethyl acetate was diluted with 100 ml of methanol, and 1 ml of 50% sodium hydroxide was added. Bring the mixture overnight. The mixture was then poured onto 160 g of ice and the mixture was diluted with water to 4 〇〇 mle with 8 〇 such as dioxane and 100 ml of hexane. The extracts were combined and evaporated to give a dark oil. The tlc using dichloromethane on cerium oxide showed a new point (RF 0.25). HPLC showed a new peak (71%) at 4. 9 minutes. Intermediate 8: 1-(2-Gasethoxy)naphthalene.

^ 〇9' A flask containing 10·8 g of intermediate 7 was treated with 60 ml of hydrazine and the solution was transferred to a 250 ml flask with a stir bar. The flask, previously containing intermediate 7, was washed with another 1 ml of smudge, which was then added to a 25 liter flask. 4.64 ml of pyridine was added with stirring and the flask was placed in an oil bath. 4.16 ml of sulfurous gas was added over two minutes at an oil bath temperature of 60C. The mixture was then warmed to an oil bath temperature of 120T:. The mixture is gently refluxed and the gas evolves. After 20 minutes, the gas escape slowed down. The oil bath was warmed to 13 °C. After 10 minutes TLC showed that the intermediate 7 was consumed and a new point (RF 0·9) (dichloromethane on the cerium oxide) appeared. The reaction mixture was poured onto 100 g of ice in 1 mL of hydrochloric acid and extracted with 5 liters of hexane. The organic layer was evaporated to give 11.9 g of m. HPLC showed a new peak (62%) at 5-7 minutes at 254 nM.

Alternatively, the intermediate 8 can be prepared by placing a sample of 17.03 g of 1-naphthol in a 25 〇mi flask, which in turn adds 45 g of potassium carbonate, 60 ml of 2-butanone, and 14 ml of 1-bromo- 2-ethane ethane. The flask was placed in a temperature of 90 ° C 152269.doc -79 - 201121958 DCM / hexane b' vigorous mixing (9). After 5 hours, the mixture was washed with hydrazine, mixture and MeOH. The TLC of the i:i DCM/& filtrate on the ceria showed product strength (RF 〇 62) and naphthol weakness (rf 〇 · 16). The filtrate was washed with 2 x 125 ml of 1 M sodium hydroxide. Remaining organic layer only

For 16.14 g of intermediates 8. ΗΡΙχ shows 93% pure (1^ 254 nM). Intermediate 9: ethyl 4-(2-ethoxyethoxy)naphthyl fluorenylacetate.

9.99 g of vaporized aluminum was placed in a 25 〇 ml flask with a stir bar. 100 ml of anhydrous dimethylacetate and 7 ml of ethyl chloroketoneacetate were added in this order. The nearly clear solution was treated with a small portion of 119 g of Intermediate 8 at a rate of mild reflux solution. After the addition, the mixture was stirred for 2 minutes, then poured onto 100 g of crushed ice, and stirred well for 15 minutes, the layers were separated, and the aqueous layer was washed with 4 ml of dichloromethane. The combined dichloromethane layers were diluted with 15 〇 95% ethanol and cooled to _2 Torr. (: </ RTI> overnight. The solid obtained was collected by filtration, washed with 25 ml of ethanol and dried in vacuo to give &lt;RTI ID=0.0&gt;&gt; Ethyl ester HpLC showed a new peak (99.7%) at 5.859 minutes. The heated filtrate was concentrated to ι ml, and cooled to provide a second crop of [4_(2_chloroethoxy) as a tan solid. Ethyl acetate of naphthalen-1-yl] ketone (3.23 g). HPLC of the second batch showed 91.2% purity. 111 &gt; 1^111 (50〇111112, €0 (:13): 9.20,111,] = 8.7, 152269.doc -80 - 201121958 7;6〇8'Th ? J=81, ^ 7,97, 1H,J=8·35 ^ 7 725 1H&gt; dd H dd; 6_82, 1H, Bu 8 3,仳4 % 2h, (iv) 7, * π 2H, J-7.2, q; 4.00, 2H, J=5.7, t; 1.44, 3H, J=7.2, t 〇 intermediate 10: [4_(2·gas ethoxylate) Base naphthalene small group] network based acetic acid.

Add 6.5 g of 50% sodium hydroxide to 75, such as 95% ethanol, and stir until clear. The mixture was diluted to MW with 95% ethanol to obtain a solution of sodium sulphate in ethanol. 3·〇8 g of the intermediate 1〇 was dissolved in 2〇(6) tetrahydrobite. Measure 0 ml of a sample of the 2 (tetra) sodium oxide solution prepared above. 2 M sodium hydroxide was added in small portions, and the mixture was sequentially treated with M d tetranitrogen, 80 ml of 95% ethanol to maintain stirring. After 5 hours, the solid was collected by filtration, washed with 2×12 ml of tetrahydrofuran and air-dried to give a 3·06 (tetra) solid. The waxy solid was placed in 100 ml of water and searched to obtain a suspension. The suspension was acidified with 10 ml of i M sulfuric acid and extracted with 3 〇 ml of chloroform. The aqueous layer was washed with an additional 20 ml of dioxane. The combined dichloromethane was thermally concentrated to 2 〇 mi, and the distillation temperature was 4 〇〇c, followed by slowly diluting with 30 ml of hexane "cooling the mixture under stirring. Filtration provided 1-91 g of the intermediate in the form of a light tan solid. MS anion (Μ-ΐ) = 277.6. HPLC showed a new peak at 4.168 minutes (99.7%). NMR (500 mHz, CDC13): 9.03, 1H, J=8.6, d; 8.80, 1H, J=8.4, d; 152269.doc -81 * 201121958 8.43, 1H, J=8.4, d; 7 74, m, Df; 7 62, ih, 6%, out, J=8.6, d; 4.53, J=5.6, t; 4.01, j=5 6 t. ’Or, prepare the intermediate l〇 as follows: use air to heat the tempo for a short period of time.

Like water. The mixture was then treated with 2 1 hydrazine sulphuric acid, diluted with water to 30 ml and cooled on ice. The mixture was diluted with water to 100... and warmed on a hot plate to give a solid suspension. The mixture was stirred and cooled in ice, then filtered and washed with water and dried then evaporated. Intermediate 11: N-(5-t-butyl-2-methoxyphenyl)_2_[4_(2·gethoxyethoxy)naphthalen-1-yl b.

1.85 g of intermediate 10 was placed in a 1 〇〇 claw flask with a stir bar. 20 ml of water-free gas was added and the mixture was placed under a septa &amp; balloon. 0.97 ml of N-mercaptomorpholine was added to give a clear, pale yellow solution. 0.84 ml of trimethylacetamidine chloride was added, and after 2 minutes, a sediment was formed. After 10 minutes, 5-tributyl-o-anisidine (1 22 g, a gas-burning solution), 1 ml of N-methylmorpholine were sequentially added, and the mixture was stirred at room temperature. 3 small 152269.doc -82- 201121958 After the time, the mixture was diluted with 20 ml of di-methane and washed with 5 〇 mi 〇% carbonic acid. The organic layer was concentrated to 30 mL and diluted with 3 mL hexanes and then cooled to -20 C overnight. The obtained solid was collected by filtration and washed with EtOAc EtOAc (EtOAc) (2-Chloroethoxy)Chao_u]_2, guanamine. MS anion (M-l) = 438, cation (M + 1) = 44 〇. Lfi NMR (5〇〇mHz, CDC13): 9.68, 1H, s; 8.82, 1H, J=8.5, d; 8.63, 1H, J=2.4, d; 8·6,1H, J=8.4, d; 8.41 , 1H, Jl=0.8, J2 = 8.4, dd; 7.68' 1H, m; 7.58, 1H, m; 7.15,1H, Jl=2.4, J2 = 8.6, dd; 6·88,1H, J=8.6,d ; 6.86, 1H, J=8.4, d; 4.51, 2H, J=5.7, t; 4.01, 2H, J=5.7, t; 3.93, 3H, S; 1.35, 9H, s. Intermediate 5: N-(5-tert-butyl-2-methoxyphenyl)_2 {4 [2 (morpholino)hexyloxy]tea-1-yl}_2·benyl amide

2.228 g of intermediate U was placed in a 75 ml thick walled Teflon (Tefl〇n) screw cap flask. 0.248 g of sodium iodide was added followed by 2 〇 mi曱oxy_2-propanol and 2.8 ml of trimethylsulfonyl morpholine. The flask was closed and at 9 Torr. Heat in a bath for 42 hours. The flask was then cooled, the contents were transferred to a 25 mL flask, and the thick-walled flask was washed with methanol (2 x 3 ml) and added to a 152269.doc •83·201121958 to 250 ml flask. The solution was diluted with water to 1 Torr for 2 minutes and the solid was collected by filtration. The solid was washed with 20 ml of water and air dried to provide 2-305 g of Ν-(5·t-butyl-2-methoxyphenyl)_2·{4·[2·(morpholin-4-yl)ethoxy Naphthyl-1-yl}-2-ketodecylamine (Intermediate 5). The HPLC retention time and the uv display sample contained 71 〇 / 〇 intermediate 5 and 27 4 〇 / 〇 remaining intermediate ^. Alternatively, Compound 5 was prepared from Intermediate U as follows: 3 g of intermediate u was placed in a 15 ml screw cap vial with a stir bar and 6 mi of morpholine was added. The mixture was warmed for 3 hours in a 1 °C oil bath. The mixture was then allowed to cool to room temperature. The solid paste was removed from the tube, diluted to 1 mL with methanol, warmed to reflux and further diluted with 25 mL water. The solid is never completely dissolved. The mixture was then ice-cooled and the solid was collected by filtration, washed with water and dried to afford compound 5 (94.99%, 25% to 95% acetonitrile, 〇 5% TFA). N-(5-Second-2-yl-2-methoxyphenyl)_2_{4_[2_(morpholin-4-yl)ethoxy]naphthalen-1-yl}-2-ketopoxime hydrochloride

N-(5-tert-butyl-2-methoxyphenyl)_2·{4·[2_(morpholine-4-yl)ethoxy]naphthalen-1-yl}-2-ketodecylamine The hydrochloride salt was prepared as shown in the above formula '' yielding 1.37 § (according to 1 1 (:, 97.46% pure). Table 1 lists the methods which can be prepared using the method of Example 1 or previously disclosed in the art. The compound provided herein. 152269.doc •84- 201121958 Table 1 No. Structure Name 1 N-(5-Tertibutyl-2-methoxyphenyl)-2-(4-(2-(N- Morpholine)ethoxy)naphthalen-1-yl)-2-ketodecylamine 2 H3CfcH3 pain wr〇N-(5-tert-butyl-3-(N,N-didecylaminosulfonyl) )-2-methoxyphenyl)-2-(4-(2-(N-morpholine)ethoxy)naphthalen-1-yl)-2-one decylamine 3 2-(4-(2 -(bis(2-hydroxyethyl)amino)ethoxy)-cai-1-yl)-N-(5-secondbutyl-2-methoxy-3-(indenylamino) Phenyl)-2-ketodecylamine 4 -fcH3 H3U N-(5-tert-butyl-3-cyano-2-methoxyphenyl)-2-(4-(2-(N-? Oleto)ethoxy)naphthalen-1-yl)-2-ketodecylamine 5 HC PH3 H3CfcH3 Marry 0 CH3 N-(5-Tertibutyl-2-methoxy-3-(decylsulfonamide) Phenyl)-2-(4-(2-(N-morpholine)ethoxy)-naphthalen-1-yl)-2-one Amine 6 η3〇^η ch3 5-t-butyl-2-decyloxy-N-mercapto-3-(2-(4-(2-(N-N-line)ethoxy)naphthalene-1- ))-2-ketoacetamido)benzamide 7 ur ch3 3 ch3 〇,ch3 5-t-butyl-N-ethyl-2-decyloxy-3-(2-(4 -(2-(N-morpholine)ethoxy)naphthalen-1-yl)-2-ketoethylamino)benzimidamide 8 H卞" is VS, 5-tert-butyl-N- Ethyl-2-decyloxy-3-(2-(4-decylnaphthalen-1-yl)-2-ketoethylamino)benzamide 152269.doc -85 - 201121958 No. Structure Name 9 H3CfcH3 %'.~〇CH3 5-t-butyl-2-decyloxy-N-(2-methoxyethyl)-3-(2-(4-(2-(N-?)) Ethoxy)naphthalen-1-yl)-2-ketoacetamido)benzamide 10 卞3 ch3 5-t-butyl-2-oxooxy-3-(2-(4-( 2- (N_? scare) ethoxy) cain-1-yl)-2-mercaptoamino)-N-(d than bit-2-yl) benzamide 11 h3c ch3 〇^« Νδ ° h3c 5-t-butyl-3-(2-(4-(2-(N-morpholine)ethoxy)-naphthalen-1-yl)-2-ketoethylamino)thiophene-2 - decyl decanoate 12 h3c ch3 combat 0 h3c 5-t-butyl-N-methyl-3-(2-(4-(2-(N-N-line) ethoxy)-naphthalen-1-yl) )-2-aminoethylamino)thiophene-2-indole 13 ch3 〇, CH3 0 N-(2-methoxy-5-mercapto-3-(methylsulfonylamino)phenyl)-2-(4-(2-(N-morpholine) ethoxylate ))Cai-1-yl)-2-indenylamine 14 ^f〇H3 N-(5-tert-butyl-2-propoxyphenyl)2-(4-methoxy-ca-1 ····2-嗣-ylamine 9 is ντο Ν-(5-cyclohexyl-2-methoxyphenyl)-2-(4-(2-(N-morpholine)ethoxy)naphthalene- 1 -yl)-2-keto-enylamine 152269.doc -86 - 201121958 No. Structure name 16 -2, N-(2-decyloxy-5-(2-phenylpropan-2-yl)phenyl) -2-(4-(2-(N-morpholine)ethoxy)naphthalen-1-yl)-2-one decylamine 17 is called fC3H3 wAvg' 〇〇, CH: 〇u 5-t-butyl -N-(cyclopropylindenyl)-2-decyloxy-3·(2·(4·曱oxycain-1-yl)-2-mercaptoacetamido)benzimidamide 18 HC H3C^-ch3 CH3 5-tert-butyl-2-methoxy-3-(2-(4-(2-(N-N-line)ethoxy)-naphthalen-1-yl)-2-one Acetylamino)-N-propyl benzomethionine 19 n N-(5-tert-butyl-2-methoxyphenyl)-2-(4-ethoxycain-1-yl)- 2-indoleylamine 20 HC P3 H3C ten ch3 H3C N-(5-t-butyl-2-methoxyphenyl)-2-W-yl-2-[4-(propan-2-yloxy) )naphthalen-1-yl]acetamide Example 3: Preparation of 5-t-butyl-2- 3- (2- (4- (6- (methylamino) pyridin-3-yl) naphthalen-1-yl) amino-2-ethyl-brewed) minced meat benzyl amine

152269.doc -S7- 201121958 Intermediate 12: 5-Terbutyl-2-methoxy-3-n-benzoic acid.

Add a catalytic amount (about 5 drops) of concentrated sulfur to a solution of 5.5 g (26 mmol) of 5-t-butyl-2-methoxybenzoic acid in 30 ml of acetic acid and 30 ml of acetic anhydride at 〇 °C. The S text 'sender adds the smoky acid (7 2 mm ο 1) dropwise. The resulting reaction solution was dropped overnight at room temperature. After the reaction, the mixture was poured into about 12 [ice_water. A white precipitate formed which was filtered and washed with water. 5 98 g of a white solid were obtained (yield 91%). Intermediate 13 : 5-tert-butyl-2-methoxy-3-nitrobenzamide.

To a solution of intermediate 12 (1.985 g, 7.84 mmol) in 50 ml of CH2C12 was added hexanes (3.5 ml </ s). After mixing for 2 hours at room temperature, the reaction mixture was evaporated to dryness. The obtained acid chloride was dissolved in 40 ml of CH2C12, followed by the addition of diisopropylethylamine (4 ml, 3 eq.), and 5%. The addition was continued overnight at room temperature and CHiCh was added to the reaction mixture. After aqueous sodium bicarbonate treatment, column purification was performed on 152269.doc •88·201121958 ISCO Optix (3x40 g® rubber column) using 0-40% B (10% sterol CHzC! 2 solution). The product was obtained as a pale yellow solid (yield: 9 〇 8%). Intermediate 14: 2-(4-bromonaphthalen-1-yl)-2-ketoacetic acid.

(4-Di-Cate-1-keto-yl-acetic acid methyl ester is prepared as described in U.S. Patent Publication No. 2005/01 07399. The treatment of 3〇7 g with 15〇g dipropylene glycol (4 bromonaphthalene-1 - Base)·keto-methyl acetate, and warmed to $. Add a solution of 5〇% sodium hydroxide in 60 ml of 95% ethanol to the mixture. Mix the mixture at 5 °C for 15 minutes. Next, 7 〇 (5) 1 μ sulfuric acid was added. The mixture was diluted with water to 5 L, and the mixture was cooled and allowed to cool. The solid was collected by filtration to provide the intervening material 14. (2·(4·bromonaphthalen-1-yl)_2 _Mercaptoethylamino)·5_Thirdyl_2-methoxybenzamide.

Intermediate 15 : 152269.doc -89- 201121958 The intermediate i3 (i.〇3i g 4·07 mmol) was reduced for 3 hours at room temperature in Pd/C and % in 40 ml of methanol. After filtration, the methanol was removed and the crude reduced compound was dissolved in 25 ml of CH2C12. Add 2.6 ml (3 equivalents) of diisopropenylethylamine. In a separate flask, intermediate 14 (136 g, ι 2 equivalent) was dissolved in 30 ml of CP^Ch, and 2.2 ml (5 equivalents) of ethylene dioxane was added, followed by the addition of a catalytic amount of DMF ^ in the chamber. The reaction mixture was stirred at ambient temperature for 2 hours and the solvent was evaporated. The obtained crude acid vapor was dissolved in 5 ml of CHzCl2, and the above amine solution was added. The mixture was stirred at room temperature for 4 hours and CHAh was added. The sodium bicarbonate aqueous solution was treated in sequence, and the ISC column was purified (3M0 g of ruthenium dioxide column, containing 〇4〇% b 50% acetic acid in acetonitrile, CHAl2) to obtain 1.08 g of a product as a yellow solid (yield : 54 9%). Intermediate 16 : N-methyl-5.(tributylstannyl)pyridine-2-amine.

A solution of 40 ml of 33% CHsNH 2 in ethanol (13 eq. After evaporation, the solid residue was suspended in CH.sub.2Cl.sub.sub.sub. The combined aqueous phases were neutralized with 2N, followed by three strips of CH2C12. The combined CH2C12 phases were washed with water and dried over sodium sulfate. Concentration gave 4.457 g of 5·bromo-N-methylpyridin-2-amine as an off-white solid (yield: 95.3%). 150 ml of anhydrous THF containing 5-bromo-N-decylpyridin-2-amine (2,805 g, 15 152269.doc 201121958 mmol) was cooled to -78t under a 1 2 atmosphere. A gamma-burning solution of 194 such as a 1.7 Μ second butyl chain (2.2 eq.) was added dropwise. The solution was continued for 30 minutes at the same temperature. Then a solution of tri-n-butyltin chloride (8.9 m Torr, 2 2 equivalents) in 15 ml of anhydrous THF was added. The reaction was stirred at _78t for 2 h and quenched with EtOAc EtOAc. Allow the temperature to slowly rise to room temperature. After the solvent was removed by evaporation, the residue was dissolved in ethyl acetate/water and was then treated with aqueous NaHC. The organic phase was dried over sodium sulfate, concentrated and purified with EtOAc EtOAc EtOAc EtOAc EtOAc (30 min)) gave 2.44 g (yield: 41%).

Intermediate 15 ( 1.633 g, 3.378 mmol), intermediate 16 (1.61 g '4.05 mmol, 1.2 eq.) and Pd catalyst (49 〇 mg '14% m〇l) were heated at 110 ° C under N2. A solution of 1 〇 ml of anhydrous toluene and 3 〇m of anhydrous dioxane was continued for 24 hours. DMF was added after evaporation. After filtration, the red solution was subjected to HPLC reverse phase purification (68 injections, method: 25-95% acetonitrile, 12 minutes). The fractions containing the product are collected. The organic solvent was removed under reduced pressure. Solid sodium bicarbonate was added to the suspension followed by the addition of ethyl acetate. The organic phase was separated and the aqueous phase was extracted again with ethyl acetate. The combined organic phases were dried over sodium sulfate. Concentration gave 727 mg 5-t-butyl-2-methoxy- 152269.doc •91- 201121958 3-(2-(4-(6-(methylamino))pyridin-3-yl)naphthalene- 1-yl)-2-ketoethylamino)benzamide (42% yield). Hydrochloride: 5-t-butyl-2-oxooxy-3-(2-(4-(6-(decylamino)pyridin-3-yl)naphthalen-1-yl)-2-one The benzylamine benzoguanamine was dissolved in CH2C12' and 2 ml of 4 M HCl in dioxane was added. CH2C12 was evaporated and anhydrous dioxane was added. The suspension was frozen and lyophilized to give 755 mg of an orange fine powder. Example 4: HCV2a chimeric luciferase virus entry assay This example shows that the compounds provided herein have activity against HCV infection. Additionally, this example shows that the compounds of the invention exhibit beneficial efficacy or cytotoxicity, or both, when compared to cyclosporin A. Preparation of cells: Native Huh7 cells were grown in a cell culture medium consisting of Dulbecco's modified Eagle's medium (Gibco BRL) supplemented with 10% fetal bovine serum (Sigma). , lx non-essential amino acid (1 〇〇χ for Ir, Scientific), 1 mM sodium pyruvate (GIBCO), and 1 penicillin/streptomycin (invitrogen). The cell line is subcultured once or twice a week. The cells were transferred by PBS washing once in a subconfluent cell by trypsinization and manually counted under a microscope using a hemocytometer. 5000 Huh7 cells were plated in each well of a 96-well culture plate. Store the plate in an incubator (37. (:, 5.0% C02) until the next time. Prepare the HCV2a chimeric infectious virus: by combining the region between the first and second putative transmembrane domains of NS2 The Core-NS2 region of the J6 genome and the NS2-NS5B of the JFH1 152269.doc •92-201121958 genome to construct the HCV 2a chimeric genome (HCV2aCh) (Jc 1 crossover; Pietschmann et al., 2006, ΡΛΜ 5) The virus was prepared by inserting Renilla luciferase (Luc), FMDV 2A protease and ubiquitin monomer sequences between the 5'NTR of HCV2a and the open reading frame of the HCV2a core protein (HCV2aChLuc). The N-terminus of Luc was fused to the 19th residue of the HCV core protein essential for HCV IRES function. Viral RNA was in vitro transcribed using the T7 Megascript kit (Ambion). DNase was added at the end of the reaction to remove the template DNA. Then, column purification (Qiagen, RNeasy mini-set) was performed. 5-10 pg of in vitro transcribed RNA was electroporated into Huh7 cells. HCV2aChLuc virus was collected by collecting supernatant after transfection. Luciferase assay The Enzyme Test System (Renilla Luciferase Assay System), Promega) and/or the Restriction Dilution Test examines the infection of the collected virus supernatant by TCID5 method SD·, 2(10)9, Μβί/ζο心Mo/·0/.) Sex. The virus-containing supernatant was aliquoted into a 50 ml conical tube and stored at -80 °C until use. Preparation of compound: A 20 mM stock solution of the test compound (100% DMSO) was serially diluted in a cell culture medium containing a final concentration of 0.1% DMSO to obtain a specific compound concentration. In detail, 3 μΐ 20 mM stock was added to 200 μM cell culture medium (0.1% DMSO) to give a concentration of 300 μM. Further, serially diluted (1:3 dilution, 7 times) 1 3 μ1 3 〇〇 μΜ in a cell culture medium (1% DMSO) to prepare a compound solution of a test compound having a final concentration of 300 η. Subsequent dilutions of (13) 300 ηΜ, weight 152269.doc •93·201121958 seven times were performed to prepare a compound solution suitable for testing, with final concentrations of 100, 30, 10, 3, 1, 0.3 and 0.1 nM. RESULTS: Infectious genotype 2a virus carrying the Renilla luciferase gene (HCV2aChLuc) was used in cell-based assays to assess the ability of Compound 1 and Compound 5 to inhibit HCV infection (circle 1) β by Taqman analysis, Immunofluorescence and western blotting and luciferase assays verify viral infectivity. 111111-7 cells were infected with HCV2aChLuc virus and continued for 〇, 0.5, 1, 3, 5, 10, 30, 48, 72 hours. Cells were harvested at various time points and luciferase activity was determined by the Renilla Luciferase Assay (promega). It was observed that luciferase activity was only slowly increased up to 5 hours after infection. However, a logarithmic increase in luciferase activity was observed between 5 and 30 hours (Fig. 2a). Addition of anti-CD81 Ab completely abolished luciferase activity, indicating that HCV2aChLuc virus infection is CD81-dependent (囷 2b). Example 3: In vitro HCVcc entry assay (validation of anti-HCV activity) Add 100 μΐ serially diluted compound solutions (1〇〇, 30, 10, 3, 1, 0.3, and 0.1 ηΜ) to cells in a 96-well culture dish in. Subsequently, 1 〇〇 Kl (TCID50/ml: about 7.0E+03) HCV2a virus was added to the cells (Μ0Ι about 〇.1). The cells were co-cultured with the virus for 72 hours in a cell culture incubator (37 ° C, 5.0% C02). Virus and compounds were removed from the cells 72 hours after infection. The cells were washed twice with P B S and then dissolved in 1 〇 μΐ per well of Passive Dissolution Buffer (Promega). The cells were lysed on the shaker for 15-20 minutes at room temperature. Transfer 50 μM of cell lysate to a new 96-well white culture dish (Costar) and add 100 μΐ of the substrate (Kephrus luciferase assay 152269.doc -94· 201121958 system, Promega) to the cell lysate Medium and immediately used to measure luciferase content in a luminometer plate reader (Veritas-Turner Biosystems). The data was processed using MS Excel and GraphP.ad Prism. Results: To test the anti-HCV activity of Compound 1 and Compound 5, Huh7 cells were co-cultured with HCV2aChRluc virus in various amounts of Compound 1 and Compound 5 for 3 days. Repeat (n &gt; 30) for testing and consistent dose-dependent inhibition was observed. Representative data is presented in Figure 3. The IC5 观察 observed for Compound 1 was 0.2 nM to 2.0 nM. IC9〇 is between 5.0 nM and 50·0 ηΜ. The estimated EC5 tethers for each experiment are described in Table 2 below. The IC5 观察 observed for Compound 5 was 0.05 nM to 0.5 nM. IC9〇 is between 5.0 nM and 15.0 nM. Table 2: IC50 of Compound 1 in HCV2aChLuc virus infection in vitro

IC5Q Results for Compound 1 IC50 (Best Fit) IC50 (95% confidence interval) 020609 0.663 nM 0.216-2.033 nM 031109 1.906 nM 0.594-6.118 nM 042009 a 1.021 nM 0.263~3.972 nM 042009 b 0.907 nM 0.281 -2.924 nM 042009 c 1.598 nM 1.122-2.276 nM 042409 1.997 nM 0.419-9.507 nM 042709 0.798 nM 0.549-1.161 nM Table 3 provides IC50 information for other compounds tested according to the method of Example 3. The IC50 value is provided in activity class "A" (IC50 less than or equal to 5 nM). The activity category "B" indicates an IC50 greater than 5 nM but less than 500 nM. The activity category "C" indicates an IC50 of 500 nM or more. 152269.doc -95- 201121958

Table 3 No. Structure Activity Category 1 卞3 奂wr〇A 2 ^f〇H3 CH3 A 3 H卞3 A 4 Hr CH3 H3CfcH3 H3C A 5 H卞3 Pain νϊΓ0 A 6 卞3 h3CW«VS 0 ch3 A 7 Hr pH3 3 ίCH3 0 〇, CH3 0 A 8 v9)CH3 0 0, CH: 0 u A 152269.doc -96- 201121958

No. Structure Activity Category 9 H3CfC3H3 咕. ~ CH3 A 10 H3CfcH3 CrW«Y2^° ch3 A 11 h3〇3VH3 5 Wei 0 h3c A 12 h3h〇YH3 u NH h3c A 13 ch3 , is wr° B 14 ^fcH3 奂V5' A 15 is v?r〇A 152269.doc •97- 201121958

No. Structure Activity Category 16 h-£, 么 wr〇h3c A 17 卞3 ^hAvX'ch3 〇〇, CH: 〇^ A 18 H3卞h3 ch3 v A 19 H3C^ch3 H3C A 20 Γ Γ H3C A 21 斗〇 〇 / B 152269.doc 98- 201121958

No. Structure Active category 22 % Ρ〇Η3. I am you. ~0 B 23 ^CX]&lt;f^CH3 B 24 H3CV/CH3 pCH3 B 25 pCH, Ογ^Ύ^ι 〇 HjC〆 B 26 h^C B 27 H3CvCH3 pCH3 ά Secret 0〇. C 152269.doc -99- 201121958 No. Structure activity class 28 Jhai 0 c 29 HaC^CH, PCH3 bud c 30 HaC^C^ PCH3 c 31 h3c, ^ch3 j nVS N^° c 32 c 33 HsCk/CK , 〇c 152269.doc 100· 201121958 No. Structure activity category 34 F% c 35 Flying capital ο 'c. c 36 ώ 0 0 c 37 CH, η3Ά /〇i /〇-0 N% c 38 order wr〇c 39 φ 〇υ c 101 - 152269.doc 201121958 No. Structure activity category 40 h3c^ch3 T^CH 4 wins 1 H3c^° 0 c 41 c 42 h3c, ^ch3 ch3 c 43 °%. Fly c 44 c 45 ο CH, ^ c 152269.doc -102- 201121958

No. Structure Active Category 46 0 Ha. Eight. C 47 h3c ch3 C 48 h3c^ch3 pCH3 /1⁄43⁄4 ~0 C 49 5露0 CH3 C 50 C 51 H3C CH3 pCH3 C 152269.doc -103- 201121958

No. Structure Active category 52 η, ο^οη, pCH, 〇丫. Vw B 53 h3c^ch3 PCH3 H^CC 54 HaCs^^ pCH B 55 h3cv.ch3 T^CH HjC B 56 H3C, ^CH3 p-CH3 CH, B 57 H3C CH3 B 104- 152269.doc 201121958 No. Structure Activity Category 58 h3c, ^ch3 c 59 c 60 ch3 h3c__^ch3 c 61 ch3 H3C—Ach3 l lei 0' c 62 h3c ch3 each wr〇B 63 ch3 win 0 c 152269.doc •105- 201121958

No. Structure Active Category 64 C 65 Β 66 Winter C 67 Bile Ο C 68 尽营 ο C 69 斋Ο C 152269.doc •106- 201121958

No. Structure Active category 70 0 c 71 H3CV.CH3 PCH3 B 72 H3C is called pCH3. Winter says 0〇B 73 NV〇% C 74 ,1ί^Ο α B 75 h3c ch3 PCH3 window h3c B 152269.doc -107- 201121958 No. Structure activity class 76 H3CX/CH3 PCH3 〇'CH3 α, c 77 PCH3 ν1Λ CH3 〇h3c'〇c 78 h3c^ch3 pCH3 ,. ~ B 79 , + this secret, two c 80 H3CVCH3 pCH3 4A\^^ H3〆 c 81 oa^0^o c 152269.doc -108- 201121958

152269.doc 109· 201121958

152269.doc •110· 201121958

152269.doc 111 · 201121958 No. Structure Active category 100 HA ^vro c 101 H3c, 0 CH, , &gt;3 c 102 CH 〇T^ 齐0 c 103 c 104 4 fasting c 105 c 152269.doc 112· 201121958

No. Structure Active species 106 HC CH3 3 at CH3 9Av%°^〇 H3C, nJ 〇 〇 H 〇 I ^n3 ch3 c 107 X taste. . B 108 ΟΊ i fast 0 B 109 呔. , CH, , &gt;^3 B 110 ◦, ch3 0 C 111 η3〇^〇η3 pCH3 hAvoc^o h3c/ 0 B 152269.doc 113- 201121958

No. Structure Active Category 112 4 Fasting C 113 &amp; Camp C 114 ~〇. C 115 小营〇 C 116 F C 117 0 0 C 152269.doc 114· 201121958

No. Structure Active category 118 J 〇 C 119 B 120 °t^^ B 121 Mai 1i^0. B 122 B 123 CH, HjC B 152269.doc -115- 201121958 No. Structure activity class 124 Fine 丫 0 c 125 c 126 rvv c 127 H3C. .CH, N c 128 H3C\^CH3 c 129 CH, CH, c 152269 .doc 116- 201121958

No. Structure Active species 130 H3C\^CH3 γΝ, C 131 C 132 h3c ch3 C 133 h3c ch3 JTch3 〇 4 ViT H3C c 134 h3cn^ch3 Mai 113⁄4 ’ B 135 H卞3 ch3 A 152269.doc 117- 201121958

No. Structure activity class 136 Chk Η H3CfcH3 f 丫, called h3c A 137 ChU H H3CfcH3 f 丫, CH3 ch3 A 138 CHU H H3CfCH3 /Tn, CH3 H3C-&quot;rT«V〇, ch3 A Example 4: HCV replicon test The HCV1 a replicon (Huh7 cells stably replicating the HCV genotype la genomic replicon) was treated with serial dilutions of test compounds for 72 hours. Taqman analysis was used to monitor replication efficiency by HCV genomic RNA amplification. Alternatively, Hutlb cells (Huh7 cells stably replicating the HCV genotype lb genomic replicon) were treated with serial dilutions of test compounds for 72 hours. Replication efficiency was monitored by ELISA assay using anti-HCV NS5A monoclonal antibody (Virogen). Results: To verify the mode of action of Compounds 1 and 5, the replicon test was used as a counter screen to rule out inhibition of intracellular viral replication. Increasing amounts of compound were seeded on HCVlb replicon cells and incubated 152269.doc-118-201121958 for 3 days. After incubation, HCV replication was monitored by ELISA for NS5 A protein expression. IFN-α was treated as a positive control for HCV replication inhibition and showed dose-dependent inhibition of HCV replication, while Compounds 1 and 5 each showed no measurable effect, indicating that anti-HCV activity may not be associated with genomic amplification or polymeric protein processing. Related (Figure 4). In addition, no cytotoxicity to Huh7 cells was observed up to 100 μΜ of Compound 1 or 500 Μ Μ Compound 5 ( FIG. 5 ). These results are consistent with Compound 5 as an entry inhibitor in the pseudovirus assay (data not shown). Example 5: BVDV plaque assay Bovine viral diarrhea virus (BVDV) is a virus closely related to HCV, which belongs to the same family, namely the flavivirus. To verify the specificity of antiviral activity, BVDV infection was performed with MDBK cells in the presence of the compounds provided herein. MDBK cells (70 to 80% confluence) were infected with the diluted virus. After adsorption at 37 ° C for 1 hour, the cells were washed once with DMEM, covered with a 1.5% low melting point (LMP) agarose (Gibco-BRL) MEM (containing 5% HS) solution, and incubated at 37 °C. To test for spotted virus, the monolayer was fixed with 3.7% formaldehyde for 2 hours at room temperature for 2 hours, the agarose plug was removed, and the monolayer was stained with crystal violet. Results: Significant inhibition of BVDV infection was not observed even at 1 μΜ of compound 5 (Fig. 6). IF analysis: After the supernatant was aspirated from the 24-well plate, 1 ml of ice-cold sterol was added to each well, and the plate was stored at -20 ° C overnight. After a while, the sterol was removed and the plate was air dried at room temperature for about 30 minutes. The plate/rehydration was then rinsed by two PBS washes (about 5 minutes/wash). To block non-152269.doc-119-201121958 specific antibody binding, cells were incubated for 1 hour at room temperature in blocking buffer (1% BSA, 0.2% skim milk in PBS). The primary antibody (mouse anti-HCV core; Affinity BioReagents, MA1-080) was diluted 1: 1 in PBS + 0.1% Tween-20 and incubated overnight at 4 ° C on a shaker (approximately 200 μΐ) Antibody / well). On the next day, each well was washed with PBS (three washes, 5 minutes each), followed by incubation with the following secondary antibody for 30 minutes at room temperature: goat anti-mouse _AlexaFluor 488 (in PBS/Tween; Molecular Probes/Invitrogen # Dilute 1:1000 in A11001. The cells were then washed three times with PBS (5 minutes each), including Hoechst staining (0.4 pg/ml; Molecular Probes/Invitrogen #H3570), to stain the nuclei. Immunofluorescence staining was performed using a 10x objective on a Zeiss fluorescent microscope. Example 6: Inhibition of virus entry into HCV la and HCV 2a » Since HCV genotype 1 is the most prevalent genotype in HCV variants, we have introduced HCVla/2a chimeric infectivity with two cell-culture adaptive mutations. Pure system. The sequence of structural proteins (including C, E1 and E2), p7 and NS2 is derived from the HCV genotype la H77 strain. The remaining non-structural proteins (NS3 to NS5B) and 3' NTR are derived from the HCV genotype 2a JFH strain. The 5'NTR is derived from HCV2aJ6 (Fig. 7). Yi and colleagues et al. proposed two cell-culture adaptive mutations (Y361H and Q1251L) that significantly enhanced the transfection of HCVla/2a chimeric virus in cell culture (J. Virol. 2007 81: 629-638). Therefore, both the HCVla/2aCh virus and the HCVla/2aChLuc virus having the Y361H and Q1251L mutations were continuously produced in Huh7 cells and used for the HCV entry assay. 152269.doc -120- 201121958 Results: The extent to which both Compound 1 and Compound 5 inhibited the HCVla chimeric virus was very similar to that observed for the HCV2a chimeric virus (Figure 8). Example 7: Effect of combination of virus entry inhibitor and ifn(R) [2. The current standard of care for the treatment of chronic hepatitis C is pegylated IFN-a (interferon alpha) and viral slaves. Since round... (rather than viral saliva) showed strong antiviral activity both in vitro and in patients, we used the in vitro HCVcc infection system to evaluate the effect of Compound 1 or Compound 5 in combination therewith. Huh7 cells were incubated with various concentrations of the individual compounds ι or interferon, or a combination of both for 72 hours, and anti-HCV activity was measured by the Luciferase Assay. The same experiment was performed on the compound s. As shown in Figure 9, the combination of Compound 1 or Compound 5 with iFN-a always results in a reduction in the degree of luciferase activity greater than that achieved by each individual agent. These results show that the combination of 5 and IFN-a and the combination of compound 5 and iFN-α each has an additive effect to a moderate synergistic effect on the inhibition of HCV infection in the cell. Example 8. The effect of a combination of a virus entry inhibitor and a viral sputum. It is known that ribavirin alone does not exhibit potent in vitro antiviral activity and is a key component of the patient's care standard. We studied the compound] and whether the combination of compound 5 and azole was antagonistic. Different amounts of each compound were co-incubated with a high concentration of diseased azole (1 5 μM). The data indicate that ribavirin alone does not significantly inhibit the infectivity of 1 agated &amp; diseased (a) and 2a chimeric virus (b). However, no antagonism was identified in the combination of compound j with ribavirin and compound 5 with ribavirin. Example 9. The effect of a combination of a viral entry inhibitor and an Hcv protease inhibitor (w95). 152269.doc -121 - 201121958 Perform a combination study of compound 1 and compound 5 spot up-IT XTC〇 ^ , i. &quot; HCV NS3 protein sea inhibitor 950. Compound 1 and the compound oxime were tested separately and tested in combination with VX-950. The ratio of the two compounds (based on the EC50 of the compound) remains fixed within the scope of administration. The cytotoxicity of individual compounds was assessed by cell viability assay based on luminescence Ατρ (Cell Titer_Gl.; pr()mega). Cell culture and luciferase compound assays were performed as described previously in Example 3. The results show the additive effect of these compounds to the micro-synergistic effect (Figure 11). Compound interactions are quantified by the method described by Chou and Talalay, relying on the median effect principle and the muitipie drug effect equation. See Ch〇u, τ c and P. Talalay, v. 1984, 22: 27 55. An isobologram is generated for each combination tested and used to determine the additive, synergistic or antagonistic effects of the inhibitor combination. The combination index (CI) was determined for each experiment using Calcusyn (Bi〇soft) under combined EC5〇, Ec” and ECm. By convention, CI&lt;0.9 is considered synergistic, c&〇9 or $丨丨 is considered as phase Add, and consider CI &gt; 1.1 as antagonism. As shown in circle 17, the value above the bar means CI. The dotted line at 〇_9 and 1.1 indicates the boundary of the additive interaction: +, synergy; Addition; - 'antagonism. Combine the index (ci) for each experiment using Calcusyn (Biosoft) at the combined EC50, EC75 and EC%. By convention, CI &lt;0.9 is considered synergistic, CI2 〇.9 or It is considered to be additive, and CI &gt; 1.1 is considered to be antagonistic. Example 10: The protease mutant (NS3: A1S6S) showed a high degree of resistance to VX-950, but not to compounds 1 and 5. 152269.doc • 122- 201121958 The A156T mutation in the NS3 coding region has been shown to confer resistance to many HCV protease inhibitors, such as 8(:11-503034〇〇〇6卩代乂卜, 8.1^1*丨吨-Plough) ' SCH- 6 (Schering-Plough) 'BILN-2061 (Boehringer Ingelheim) and VX-950 (Vertex). Therefore, we introduced A156S in the main chain of the HCV2aChLuc genome. The infectivity of the mutant virus in the presence of the compound was investigated and, as expected, HCV2aChLuc (NS3: A156S) showed high resistance to VX-950 as compared to wild-type HCV2aChLuc. However, in Compound 1 or Compound 5 No significant difference was observed in the inhibition of the infectivity of the wild type virus and the mutant virus, indicating that there was no cross-resistance between the protease inhibitor and the virus entry inhibitor as expected (Figure 12). Example 11: SR-B1 is a compound Potential targets for 1 and 5. Compound 5 increases HDL content in mice and humans but not in SR_B1 knockout mice (A. Tall, preparation of manuscripts) indicating its dry-to-SR-B 1 pathway. SR-B1 is known to be an essential cellular receptor required for HCV entry, so we are concerned whether it is known whether compounds 1 and 5 inhibit HCV entry via SR_B1. The interaction between HCV E2 protein and SR-B1 is localized via E2. The hypervariable region 1 in the N-terminal region of bilirubin appears. Zhong and colleagues report that the glycine-to-arginine mutation at position 451 (G451R) in E2 promotes JFH4 infectivity (J. snoring/. 200&lt;5, don't _·&quot;(10)2). Grove and colleagues Description JFH-1 G451R mutant has a reduced dependency on the SR-B1 and enhance binding to the CD81 (· / · Viol. 2008, FIG. 13b). We introduced the E2:G451R mutation into the backbone of HCVhCh (Fig. 13a) to test whether this mutation can alter the inhibitory effect of compounds 1 and 5 on SR-B1-mediated HCV entry. -123- 152269.doc 201121958 IFN-α was used as a control to show that the sensitivity of the E2 canine variant virus to compound inhibition was derived from the virus entry process rather than the sensitivity of the parental virus. The copy process. The E2 mutant virus did show greater resistance to compound j relative to the parental type of virus, as shown in the luciferase assay for viral infectivity (囷14). However, the response of the parental and £2 mutant viruses to IFN-α showed a very similar pattern, suggesting that the anti-Hcv activity of compound j is more likely to be associated with the viral entry step than the other steps of the hCv life cycle (Figure 14). As shown in circle 15, the £2 mutant virus did show greater resistance to the chemical 5 compared to the wild type virus, as shown in the Taqman assay of the viral rna replica. Two 24-well plates were seeded at 4 x 104 cells/well. The next day's aspirate the cell culture supernatant and expose the cells to wild type 11 (^23(:11 (black bars) and mutant 1^(:¥2&(:11(£2:045111))) Bar). Add about 250 μM cell culture virus to each well (about lxl〇4 tcid/well or moi about 〇·25). Immediately after the virus is added to the well, 2.5 μΐ 1〇〇 concentration of the compound Add to each well and mix multiple times with a 100 μl pipette tip to achieve final compound dilution: 〇ηΜ, 5 ηΜ, 15 ηΜ, 50 ηΜ, 150 ηΜ, and 500 ηΜ. Test compound 5. Continuous treatment Culture plate. After adding virus and compound, place the culture plate in the incubator for about 3.5 hours (37 ° C, 5% C 〇 2) » After incubation, replace the supernatant with fresh medium (about 1 ml / well) The plate was placed back in the incubator. After 24 hours (about 27.5 hours after the virus was exposed to the cells), the cells were washed once with 1 ml of PBS, followed by treatment of the cells for Taqman analysis. Immunofluorescence was used as a reading, E2 mutant Also shown as compound 5 compared to wild type disease 152269.doc -124- 201121958 More resistant (Figure 16).Example 12: Combination therapy of Compound 5 with anti-HCV compounds. Compound 5 was evaluated in combination with the following anti-HCV compounds in the HCV genotype-2a infectious virus system: interferon-alpha, virus Oxazole, BILN2061, VX95 0, VX1 and 2'-C-methyladenosine. Zhiquei ##. Make human liver tumor Huh-7_5.1 cells or Huh7 cells supplement at 37 ° C and 5% C02 Dube with 2 mM L-glutamic acid, 1 mM sodium pyruvate, 1 X non-essential amino acid mixture, 100 units/ml penicillin, 100 gg/ml streptomycin and 10°/fetal bovine serum It has been modified to grow in Eagle's medium. 苈## Invitation. The chimeric full-length construct pFL-JCl has been previously described, consisting of a structural gene from the J6CF isolate and a non-structural gene from the JFH1 isolate. GT2a/2a chimera. See Backes et al, J. Virol. 2010, 84: 5775-89; Schaller et al, J. Virol., 2007, 81:4591-603; Koutsoudakis et al, J. Virol. 2006, 80:5308-20; Pietschmann et al, Proc. Natl Acad. Sci·, 2006, 103: 7408-13. The firefly luciferase gene has been inserted into pFL-Jcl for application. Replication of the virus reported body mass pFL-Jcl-luc color. See Amako et al., J. Virol. 2009, 83: 9237-46. In particular, the pFL-JCl-luc construct can be used to visualize infectious HCV cell culture systems to test novel HCV inhibitors, including entry inhibitors, in vitro using luciferase expression. Attacked and attacked CK. Jcl-luc or HCV2a/2aChRluc RNA was transcribed in vitro using the T7 RiboMAXTM Express Large Scale RNA Production System (Promega). After RNA clearance (Qiagen RNeasy Small 152269.doc -125 - 201121958 kit), transfection was performed as previously described [26]. Place 400 μl of Huh-7.5.1 or Huh7 cell suspension (107 cells/ml) in a 0.4 cm cuvette containing 1 〇Rg Jcl-luc or HCV2a/2aChRluc RNA' and use a single square wave at Electroporation (Bio-Rad Gene Pulser System) at 260 V and 25 m pulse length. The cells were plated in 15 cm tissue cultures (Corning) and the supernatant was collected and concentrated using a centrifugal filter (Amicon 100K, Millipore). Fully set to attack CK. The original Huh-7_5.1 cells coated in a 96-well culture plate were infected with a 10-fold serial dilution of the infectious supernatant. The plants were incubated with the cells overnight at 37 ° C, then replaced with fresh complete medium and incubated for an additional 72 hours. Cells were stained with a single mouse anti-CORE IgG antibody (#MAl-080, Thermo Scientific) at a dilution of 1:300' followed by binding of multiple goat anti-mouse IgG to HRP at 1:100 dilution at room temperature ( # 12-349, Millipore) - 1 hour incubation. In the last and last second wells of the dilution series that produced the CORE positive focus, the average number of focal points counted under the microscope was calculated for infectious power. Extravagance #箱/6合#活捡发发β As described previously, cell culture and luciferase compound assays were performed. See Wyles et al., J. Virol. 2007, 81:3005-8; Wyles et al., Antimicrob Agents Chemother. 2009, 53:2660-2; Griinberger et al., J. Infect. Dis. 2008, 197:42-5 Wyles et al., Antimicrob Agents Chemother, 2008, 52:1862-4. Briefly, Huh7.5.1 cells were seeded at a density of 10,000 cells per well in 100 μΐ medium in 96-well plates. After overnight incubation for attachment, ΜΟΙ0.01 of Jcl-luc virus was added to wells containing 152269.doc • 126·201121958 compounds containing no regulatory concentrations. All conditions are operated in triplicate. After 24 hours, the medium was aspirated and replaced with 100 μΐ of complete medium containing the same concentration of the compound, followed by incubation for another 48 hours. Luciferase assay was performed according to the manufacturer's instructions (Bright-Glo; Pr〇megap using a microplate luminometer (Veritas microplate luminometer; Turner Bi〇 systems) to measure luciferase activity. Under each condition The relative light unit (RLu^s is reported in the form of the mean value of the three holes ± the standard error of the average value. The active concentration of the compound 5 and other anti-HCV compounds is independent of the standard concentration (ECso). Measured and used to set the concentration range for the synergistic experiment. Test compound 5 in combination with each of the anti-HC V compounds listed above at two-fold serial dilutions above and below EC. Compounds in the HCV2a/2aChRluc system Virus wow' or yx9s〇〇 100 μΐ serially diluted compound solutions (100, 3〇, 1〇, 3, 1 '〇3 and 0.1 ηΜ) were seeded on Huh-7 cells in 96-well culture plates. Add 100 μl (Τ(:5Ι〇 about 〇.6) HCV2a/2aChRlu(^ to the cells. After 72 hours of co-cultivation, determine the expression of Renilla luciferase (the Renilla luciferase assay) , Pr〇mega) and reported in the form of relative light units (RLU). Quantitative determination of compound interactions based on the intermediate effect principle described by Chou and Talalay. Chou T., Talalay P” Adv Enzyme. Regul., 1984, 22:27·55. At EC5, 75 and %9. Next, use Calcusyn (Bi〇soft) to determine the combination index (匸丨) for each experiment. Evaluate five replicates of each condition. Consider CI&lt;〇9 as synergistic, 9 and S1.1 as additive' and CI &gt;11 was considered to be antagonistic. Using the Jcl-Luc test system, compound 5 and each companion compound 152269.doc -127- 201121958 EC50 (standard error of soil mean) are listed in Table 4. Table 4 · Anti-HCV compounds In vitro inhibitory activity against Jcl-luc and cytotoxicity compound EC5〇(nM) CC50 (μΜ) Compound 5 20.19±1.37 &gt;100 Interferon-α 3.0U0.39 IU/ml &gt; 100 IU/ml BILN2061 492.44± 56.69 35 2'-C-decyl adenosine 251.76±33.54 &gt; 100 VX1 88.14±12.73 100 magnetic 屌 紫 紫 紫 紫. The results of the synergistic experiment are the combination of compound 5 and the tested anti-HCV compound combination The expression of the index (CI) is shown in Figure 18. In Figure 1, the value above the bar means CI.The error bars represent the mean standard error of the CI. The two lines at 0.9 and 1.1 indicate the boundary of the additive interaction. +, synergy; gentleman, additive effect; -, antagonism. ED5〇, ED75 and ED9〇 refer to EC5Q, EC75 and EC9 of each compound, respectively. The combination index below. Compound 5 did not antagonize any of the compounds studied. Specifically, Compound 5 is compatible with interferon-a, BILN2061, and 2'-C-methyl gland (CI is 1.00, 0.98, and 1.09) at 50% effective dose (ED5Q). Synergistic effects were observed with all tested compounds at 75% effective dose (ED75) and 90% effective dose (ED9Q). The combination of Compound 5 and VX1 showed a consistent synergy at ED50, ED75 and ED90. Similar results were obtained in the HCV2a/2aCHRLuc system, in which compound 5 also showed synergy with VX-950. See Figure 19. The no compound combination showed cytotoxicity at the highest concentration used in the synergistic study. /6合#5典斿#Wow. Although ribavirin alone does not exhibit potent in vitro antiviral activity, it is a key component of patient care standards. Compound 5 of different amounts 152269.doc -128- 201121958 was co-incubated with high concentration ribavirin (15 μΜ), and ribavirin alone did not significantly inhibit the infectivity of the 2a chimeric virus. See Figure 20. However, no antagonism was identified in the combination of Compound 5 and ribavirin. Example 14: Resistance studies of Compound 5 and VX-950. The viral resistance of Compound 5 and VX-950 in the NS3 protease mutant (A156S) was evaluated. Alanine mutations at position 156 of the NS3 coding region have been shown to confer resistance to many HCV protease inhibitors, such as SCH-503034 (boceprevir, Schering-Plough) 'SCH-6 (Schering-Plough) 'BILN-2061 (Boehringer Ingelheim) ) and VX-950 (Vertex). Therefore, the A15 6S mutation was inserted into the main chain of the HCVSaChLiic genome to investigate the infectivity of the mutant virus in the presence of Compound 5 and VX-950. As expected, HCV2aChRLuc (A156S) showed a high degree of resistance to VX-950 as compared to wild-type HCV2aChRLuc. In contrast, no significant difference in Compound 5 inhibition of wild type virus infection with mutant virus was observed, indicating a lack of expected cross resistance between the protease inhibitor and the virus entry inhibitor. </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; While the invention has been described in terms of the preferred embodiments embodiments illustrated embodiments Therefore, the scope of the invention is intended to be limited only by the scope of the following claims, including the equivalents thereof. BRIEF DESCRIPTION OF THE DRAWINGS 152269.doc -129- 201121958 Figure 1 is a schematic representation of the HCV2aChLuc (HCV2aJ6/JFH chimeric Renilla-luciferase pure lineage) genome; Figure 2 shows the characterization of HCV2aChLuc virus infection in cell culture; Figure 3 is a graphical depiction of the dose-dependent inhibition of HCV2aChLuc virus entry by Compound 1 and Compound 5; Figure 4 shows Compound 1 and Compound 5 and unduly inhibiting HCV RNA replication; Figure 5 shows that Compound 1 and Compound 5 do not affect Huh7 cells. Moderate toxicity; Figure 6 shows that Compound 1 has no detectable inhibitory effect on BVDV infection; Figure 7 is a schematic structure of HCVla/2a chimera with adaptive mutation; Round 8 shows inhibition of each of Compound 1 and Compound 5 Two HCVs of the structural protein of genotype la or 2a; Figure 9 is a graphical depiction of the effect of Compound 1 or the combination of Compound 5 and IFN-a (interferon-α); Figure 10 is Compound 1 or Compound 5 and ribavirin Graphical depiction of the effect of the combination; Figure 11 is a graphical depiction of the effect of Compound 1 or Compound 5 in combination with the HCV NS3 protease inhibitor VX950; Round 12 shows HCV2aChLuc (NS3: A156S) The body is highly resistant to VX950 but not to compounds 1 and 5; 圊13 is (a) a schematic structure of the E2:G451R mutation introduced into the HCV2aCh backbone, and (b) shows that the E2:G451R mutation is reduced to SR-B1 Dependence and increase 152269.doc -130- 201121958 Strong binding to CD8 1; Figure 14 shows antiviral activity of compound 1 with 11(:¥2&amp;(^(£2:045111) mutant virus; 15 shows the antiviral activity of compound 5 with the HCV2aCh (E2:G451R) mutant virus; Figure 16 shows immunofluorescence readings showing the antiviral activity of compound 5 with the HCV2aCh (E2:G451R) mutant virus; 17 is a graphical depiction of the synergistic effect of Compound 1 or Compound 5 in combination with HCV NS3 protease inhibitor VX950; Figure 18 shows the combination index (CI) of Compound 5 in combination with various anti-HCV compounds; Figure 19 shows Compound 5 and VX-950 Combined combination index (CI) and relative luciferase activity of the compound; Figure 20 shows the relative luciferase activity of compound 5 alone and ribavirin and combinations thereof; and Figure 21 shows the HCV2aChRLuc (A156S) protease mutant pair VX-950 instead of compound 5 Sexual 152269.doc -131 -

Claims (1)

201121958 VII. Patent Application Range: 1. A method for treating hepatitis C virus infection in a host, comprising administering an effective amount of a compound of the formula τ or a formula π, a stereoisomer thereof, to a host infected with the hepatitis C virus, Or a pharmaceutically acceptable salt thereof, h3c|"ch3 X is R3 R1 is fluorenyl, ethyl, isopropyl, · L〇h, R is Ci-Cs alkyl 'C5-C8 cycloalkyl or c7-Ci aryl aryl; R3 is hydrogen, cyano , -CONHR6, -NHS02R7 or -S〇2N(R8)2; alkyl; alkoxy or -N(R8)2; R is 2-n to 0-yl or Ci-C6 alkyl' The carbon atom is optionally replaced by an oxygen atom; R7 is C1-C4 alkyl, CH2CF3, benzyl or phenyl; R8 is Ci-C4 alkyl; R9 is bromine or 6-(methylamino)pyridine-3- R10 is hydrogen or -CONHR11; and 152269.doc 201121958 Rn is hydrogen or c丨-C4 alkyl; the restriction is if R3 is -N group; HS〇2R and the ruler is methyl, then R丨 is not limited The condition is that if R10 is the main '', 虱, then 11 is 6-(methylamino)pyridin-3-yl; the restriction is that if R1 丨, then R is bromine. L. Other restrictions are if R2 is methyl, shell, not -NHS〇2R9. Signed 3. If request item 1 $古' other restrictions strip 侔 gas # Ρ 2 &amp; β甘α is -Qing (four), take, The condition of a f is the right ^ methyl group and 4. If the claim 1 is ancient, the soil R2 is not a methyl group. ' 'The restriction condition is if R3 -nhs〇2R 5. If the request item 1 $古Κ9Λ ψ ,, the other restrictions are if r3 is -nhso2r R is 曱 ' ', then r2 is not 曱. 6. If the request item 1 $士, +一一N0. The method 'wherein R1 is methyl, ethyl or isopropyl. 7. The method of claim 1, wherein R is isopropyl or 8. The method of claim ,, wherein R2 is methyl, or b Base + stupidyl ethyl. butyl-butyl, 9. As requested, the square--1- laughing I is a second butyl group, a cyclohexyl group or a 1. base ethyl group. The method wherein r2 is a third butyl group. u. The method of claim 1 wherein tR3 is gas. 12. The method of claim 1, wherein R3 is -1^8〇2119 and 119 is sulfhydryl. Doc A and R3 R3 and or base unit 201121958 13. 14. 15. 16. 17. 18. 19. 20. 21. The method of claim 1 &gt; ancient, also ^ 4 ,, where R is a third butyl group Such as the request item kt, soil ^ 5 m, the method, wherein the rule is methoxy or dimethylamino. The method of methoxy oxime 1, wherein R6 is fluorenyl, ethyl, propyl, soil, methylene Cyclopropyl or 2-pyridyl. A method of claim 7, wherein R is methyl or ethyl. The method of month length item 1, wherein each R8 is a methyl group. The method of claim 1, wherein Ru is a mercapto group or an ethyl group. The method of claim 18, wherein R9 is 6 (the amide group is more than the bite _3 • the method of claim 1 wherein R is soil; r &gt; 1 0 ^ is -CONHR丨丨; and R is Ci- The method of claim 1, wherein the compound or a pharmaceutically acceptable salt thereof has the following formula: 〇 22. The salt of the method of claim 1 having the formula: wherein the compound or pharmaceutically acceptable 23. The method of claim 1, wherein the compound or a pharmaceutically acceptable salt thereof has the formula: 24. The method of claim 1, wherein the compound or a pharmaceutically acceptable salt thereof has the formula: 25. The method of claim 1, wherein the compound or a pharmaceutically acceptable salt thereof has the formula: 26. The method of claim 1, wherein the compound or a pharmaceutically acceptable salt thereof has the formula: 152269.doc 201121958 27. The method of claim 1, wherein the compound or a pharmaceutically acceptable salt thereof has the formula: 28. The method of claim 1, wherein the compound or a pharmaceutically acceptable salt thereof has the formula: h3c 29. The method of claim 1, wherein the compound or a pharmaceutically acceptable salt thereof has the formula: The method of claim 1, wherein the compound or the pharmaceutically acceptable salt of 152269.doc 201121958 has the formula: 3. The method of claim 1, wherein the compound or a pharmaceutically acceptable salt thereof has the formula: 32. The method of claim 1, wherein the compound or a pharmaceutically acceptable salt thereof has the formula: 33. The method of claim 1, wherein the compound or a pharmaceutically acceptable salt thereof has the formula: 152269.doc 201121958 3 4. The method of claim 1, wherein the compound or a pharmaceutically acceptable salt thereof has the formula: 3. The method of claim 1, wherein the compound or a pharmaceutically acceptable salt thereof has the formula: 3. The method of claim 1, wherein the compound or a pharmaceutically acceptable salt thereof has the formula: 3. The method of claim 1, wherein the compound or a pharmaceutically acceptable salt thereof has the formula: 152269.doc 201121958 3. The method of claim 1, wherein the compound or a pharmaceutically acceptable salt thereof has the formula: 39. The method of claim 1, wherein the compound or a pharmaceutically acceptable salt thereof has the formula: The method of claim 1, wherein the compound or a pharmaceutically acceptable salt thereof has the formula: 152269.doc 201121958 4 1. The method of claim 1, wherein the compound or a pharmaceutically acceptable salt thereof has the formula: 42. The method of claim 1, wherein the compound or a pharmaceutically acceptable salt thereof has the formula: 43. The method of claim 1, wherein the compound or a pharmaceutically acceptable salt thereof has the formula: 44. The method of claim 1, wherein the compound or a pharmaceutically acceptable salt thereof has the formula: 152269.doc 201121958 45. Among the therapeutic hosts. A method of infecting a hepatitis B virus comprising administering an effective amount of a compound such as a compound or a compound of the formula II, or a stereoisomer thereof, or a pharmaceutically acceptable &lt; a salt of 'and-or a plurality of antiviral agents selected from the group consisting of: or alternatively administered: a nuclear polymerase inhibitor, a non-nuclear polymerase inhibitor, a protease inhibitor, a cyclophilin modulator, an interferon And ribavirin. The method of claim 45, wherein the formula or the compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered in combination or alternately with the interferon. 47. The method of claim 45 wherein the formula or the compound of the formula (10) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof is administered in combination or alternation with interferon and ribavirin. 48. A compound of formula j or formula η, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a hepatitis C virus infection. 49. Kind of 4 items! Or the use of the formula π, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of hepatitis C virus infection. I52269.doc •10·